11-Substituted-desA-pregnanes and derivatives thereof

ABSTRACT

This invention is directed to 11-substituted-desA-pregnanes and derivatives thereof which are useful as intermediates in the production of 9β,10α-known steroids of the pregnane series. These latter compounds can be utilized as progestational and salt-retaining agents.

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 306,496,filed November 14, 1972, now U.S. Pat. No. 3,380,831, entitled"11-SUBSTITUTED-DESA-PREGNANES AND DERIVATIVES THEREOF", which is acontinuation of application Ser. No. 736,569, filed June 13, 1968, nowabandoned, entitled "11-SUBSTITUTED-DESA-PREGNANES AND DERIVATIVESTHEREOF", which is a division of application Ser. No. 499,094, filedOct. 20, 1965, now U.S. Pat. No. 3,574,761, entitled "INTERMEDIATES ANDPROCESSES", which is a continuation-in-part of application Ser. No.400,206, filed Sept. 29, 1964, now U.S. Pat. No. 3,412,107, entitled"INTERMEDIATES AND PROCESSES".

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel chemical intermediates and processesuseful in the preparation of steroids. Natural steroids possess a9α,10β-stereochemical configuration. Steroidal compounds possessing theunnatural 9β,10α-configuration represent a pharmaceutically valuableclass of compounds which, even though numerous members are known in theart, cannot be obtained by totally classical chemical means. In fact,the only known methods for obtaining steroids possessing the unnatural9β,10α-configuration involve at least one photochemical reaction. Suchphotochemical reactions involve irradiation with ultraviolet light ofstrong intensity for long periods of time and, in comparison with purelychemical reactions, are very inefficient and give only small yields.

It is an object of the present invention to provide intermediates andprocesses which enable the preparation of 9β,10α-steroids without thenecessity of proceeding through a photochemical reaction. It is also anobject of this invention to provide novel intermediates and processeswhich will enable the further exploration of steroids having theunnatural 9β,10α-configuration. It is also an object of this inventionto provide novel 9β,10α-steroids.

The novel intermediates and processes of this invention are valuable andprovide a new synthetic route completely of a classical chemical nature,i.e. involving no photochemical reaction, for converting steroids havingthe normal configuration into steroidal compounds possessing theunnatural 9β,10α-configuration.

In one aspect, the novel intermediates and processes of this inventionenable the preparation of 9β,10α-steroids of the androstane series ofthe formula ##SPC1##

Wherein R₁ is, individually, selected from the group consisting ofhydroxy and lower alkanoyloxy; R₂ is, individually, hydrogen or loweralkyl and R₁ and R₂, taken together, are selected from the groupconsisting of (17β-OH, 17α-lower alkanoic acid lactone) and oxo; R₃ isselected from the group consisting of hydrogen, lower alkyl, hydroxy andlower alkanoyloxy; Y is selected from the group consisting of hydrogenand lower alkyl and X is a substituent in the 6- or 7 -position selectedfrom the group consisting of hydrogen, lower alkyl, lower alkylthio,lower alkanoylthio and halogen.

Compounds of formula I are useful as anabolic agents.

Other 9β,10α-androstanes, the preparation of which is enabled by theintermediates and processes of this invention, are of the formulae##SPC2##

wherein R₁, R₃, Y and X have the same meaning as above. Compounds offormula III are useful as progestational agents and compounds of formulaII are useful as anti-androgenic agents.

In another embodiment of this invention, the novel compounds andintermediates provided by this invention enable the preparation of9β,10α-steroids of the 17β-pregnane series of the formula ##SPC3##

wherein Y and X have the same meaning as above; R'₃ is selected from thegroup consisting of hydrogen, lower alkyl, fluoro, hydroxy and loweralkanoyloxy; R₅ is selected from the group consisting of hydrogen andhalogen; and R₆ is selected from the group consisting of hydrogen, loweralkyl, hydroxy and halogen.

Compounds of formula IV are useful as progestational agents.

Other 9β,10α-steroids of the 17β-pregnane series, preparable from thenovel compounds and process of this invention, are of the formula##SPC4##

wherein R'₃, R₆, Y and X have the same meaning as above.

Compounds of formula V are useful as salt-retaining agents, i.e. areuseful in the treatment of Addison's disease.

As used herein, the term lower alkyl comprehends both straight andbranched chain saturated hydrocarbon groups, such as methyl, ethyl,propyl, isopropyl and the like. Similarly, the term lower alkanoylcomprehends groups such as acetyl and the like, and the term loweralkanoyloxy comprehends groups e.g. formyloxyacetoxy and the like. Inthe same manner, the term lower alkenyl comprehends groups such as vinyland the like, and the term lower alkynyl comprehends groups such asethinyl and the like. Halogen comprehends all four halogens, i.e.iodine, bromine, chlorine and fluorine.

The expression "( 17β-OH, 17α-lower alkanoic acid lactone)" refers to aconfiguration on the C-17 carbon atom illustrated as follows: ##SPC5##

wherein W is lower alkylene, e.g. polymethylenes such as ethylene,propylene or the like.

With respect to substituents in the 6- and 7-position, preferredcompounds are those having hydrogen or lower alkyl in 6- or 7-position,and those having halogen in the 7-position.

In one aspect, this invention comprises a method for the preparation of9β,10α-androstanes of formulae I-III and of 9β, 10α-17β-pregnanes offormulae IV-V which comprises the hydrogenation ofdesA-androst-9-en-5-ones or of desA-17β-pregn-9-en-5-ones to9β,10β-desA-androstan-5-ones or 9β,10β-desA-17β-pregnan-5-ones,respectively, followed by condensation with a lower alkyl vinyl ketonewith methyl or ethyl vinyl ketone preferred (as well as substitutestherefor such as 1-tertiary amino-3-butanone, 1-tertiaryamino-3-pentanone and quaternary ammonium salts thereof),1-Q-butan-3-one, 1-Q-butan-3-one lower alkylene ketal, 1-Q-butan-3-ol,esterified 1-Q-butan-3-ol, 1-Q-butan-3-ol ether, 1,3dichlorobut-2-ene,1,3-dichloropent-2-ene, 1-pentan-3-one, 1-Q-pentan-3-one lower alkyleneketal, 1-Q-pentan-3-ol, esterified 1-Q-pentan-3-ol or 1-Q-pentan-3-olether, which condensation yields the desired 9β,10α-steroids. The symbolQ is is bromine, chlorine or iodine, with the former two beingpreferred. This invention also provides a number of different methodsfor the preparation of said desA-androst-9-en-5-one ordesA-17β-pregn-9-en-5-one starting materials from natural steroids.

In one embodiment, a steroid of the 3-oxo-androst-4-ene or3-oxo-17β-pregn-4-ene series is subjected to an oxidative ring openingof the A-ring yielding a 5-oxo-3,5-seco-A-norandrostan-3-oic acid or a5-oxo-3,5-seco-A-nor-17β-pregnan-3-oic acid, which 3-oic acid can thenbe converted to a mixture of a 10α-desA-androstan-5-one and a10β-desA-androstan-5-one or a mixture of a 10α-desA-17β-pregnan-5-oneand a 10β-desA-17β-pregnan-5-one. The conversion of the 3-oic acid tothe desA-compound can be effected either by pyrolysis of a salt of said3-oic acid or via the enol lactone, i.e. a 4-oxoandrost-5-en-3-one or a4-oxo-17β-pregn-5-en-3-one, which upon reaction with a Grignard reagentgives an aldol, which in turn can be converted into the desireddesA-compound. The desA-compound can then be converted into the startingmaterial desA-androst-9-en-5-one or desA-17β-pregn-9-en-5-one via atwo-step sequence of halogenation and dehydrohalogenation.

In another embodiment of this invention, desA-androst-9-en-5-one ordesA-17β-pregn-9-en-5-one starting materials can be prepared from11-hydroxy steroids of the 3-oxo-androst-4-ene or 3-oxo-17β-pregn-4-eneseries. This can be effected in a variety of ways. In one approach, an11-hydroxy group of a steroid of the 3-oxo-androst-4-ene or3-oxo-17β-pregn-4-ene series is converted into a leaving group, forexample, a sulfonic acid ester or carboxylic acid ester. Oxidative ringopening of the A-ring of the thus formed 11-(esterifiedhydroxy)-containing compound yields the corresponding 11-(esterifiedhydroxy)-5-oxo-3,5-seco-A-norandrostan-3-oic acid or 11-(esterifiedhydroxy)-5-oxo-3,5-seco-A-nor-17β-pregnan-3-oic acid which uponpyrolysis of a salt of said 3-oic acid yields the desireddesA-androst-9-en-5-one or desA-17β-pregn-9-en-5-one starting material.

A further approach involves formation of an11-hydroxy-desA-androstan-5-one or 11-hydroxy-desA-17β-pregnan-5-onefrom an 11-hydroxy steroid of the 3-oxo-androst-4-ene or3-oxo-17β-pregn-4-ene series via an oxidative ring opening of the A-ringof said 11-hydroxy steroid which yields an11-hydroxy-5-oxo-A-nor-3,5-secoandrostan-3-oic acid 3,11-lactone or an11-hydroxy-5-oxo-3,5-seco-17β-pregnan-3-oic acid 3,11-lactone which, inturn is converted into a salt of the corresponding keto acid which saltupon pyrolysis gives the 11-hydroxy-desA-androstan-5-one or11-hydroxy-desA-17β-pregnan-5-one. Esterification of the 11-hydroxymoiety of the so-obtained compound with an acid moiety yields an11-(esterified hydroxy)-desA-androstan-5-one or an 11-(esterifiedhydroxy)-desA-17β-pregnan-5-one which upon elimination of the leavinggroup (i.e., the esterified hydroxy moiety) gives the desireddesA-androst-9-en-5-one or desA-17β-pregn-9-en-5-one starting material.Though, in the above reaction sequence either 11α-OH or 11β-OH startingmaterial steroids can be used, it is preferred to use 11α-OH startingmaterials.

As will be appreciated from the above discussion, neither the specificreaction steps nor the reaction sequences of this invention involve anymodification of substituents found in the 16- and/or 17-position of thestarting material natural steroids. However, in order to obtainunnatural 9β,10α-steroids of formulae I-V, it is necessary or desirableto protect certain of the 16- and/or 17-substituents against one or moreof the reaction steps involved. It is also convenient to initiallyprotect such a substituent in the starting material natural steroid andmaintain the substituent in its protected form throughout the entirereaction sequence, regenerating the desired substituent only when thesteroid of formulae I-V possessing the unnatural 9β,10α-configuration isobtained. On the other hand, it is sometimes convenient to insert aprotecting group only before a certain reaction step or sequence ofreaction steps. Said protecting group can then be maintained until thefinal reaction step or can be split off at some intermediate stage. Theprotecting groups can be inserted and split off by means know per se.The desirability of having protecting groups present will be furtherdiscussed below when the specific reaction steps are discussed indetail. The various substituents which are susceptible to beingprotected are exemplified by the 16-hydroxy group in a compound of anyof formulas I-V, the 17β-hydroxy group in a compound of any of formulasI-III, the 17α-hydroxy or 20-oxo group in a compound of any of formulasIV-V, the 21-hydroxy group of a compound of formula V or the 17-oxogroup of a compound of formula I.

The 17-oxo or 20-oxo group is suitably protected by ketalization, i.e.,by reaction with a lower alkanediol, to yield a 17-lower alkylene dioxyor 20-lower alkylene dioxy compound, i.e., a 17-ketal or a 20-ketal.

The 16-hydroxy, 17α-hydroxy, 17β-hydroxy or 21-hydroxy moieties can beprotected by esterification and/or etherification of the hydroxy group.Any available acid which will form an ester that can subsequently behydrolyzed to regenerate the hydroxy group is suitable. Exemplary acidsuseful for this purpose are lower alkanoic acids, e.g. acetic acid,caproic acid, benzoic acid, phosphoric acid and lower alkanedicarboxylic acids, e.g. succinic acid. Also, protection for the16α-hydroxy, 17α-hydroxy, or 21-hydroxy substituent can be effected byforming the lower alkyl ortho ester thereof, i.e. 16α,17α- or 17α,21-lower alkyl ortho esters. A suitable ether protecting group is, forexample, the tetrahydropyranyl ether. Others are arylmethyl ethers suchas, for example, the benzyl, benzhydryl and trityl ethers, or α-loweralkoxy-lower alkyl ethers, for example, the methoxymethyl, or allylicethers.

In compounds containing the dihydroxyacetone side chain at C-17 (forexample, compounds of formula V wherein R₆ is hydroxy), the side chainat C-17 can be protected by forming the 17,20; 20,21-bis-methylenedioxygroup or by forming a 17,21-acetal or ketal group, or by forming a17,21-diester. The 17,21-acetal or ketal and 17,21-diester hinder the20-ketone group and minimize the possibility of its participating inunwanted side reactions. On the other hand, the17,20;20,21-bis-methylenedioxy derivatives actually convert the ketoneto a non-reactive derivative. When both a 16α-hydroxy and 17α-hydroxysubstituent are present, these groups can be protected via formation ofa 16α,17α-acetal or ketal. The various protecting groups mentioned abovecan be removed by means known per se, for example, by mild acidhydrolysis.

In compounds wherein there is present neither a 17α-hydroxy nor21-hydroxy substituent but there is present a 20-oxo group, the 20-oxogroup can be protected via reduction to the corresponding carbinol(hydroxy) group. Thus, for example, the 17-acetyl side chain can beprotected via conversion to a 17-(α-hydroxyethyl)-side chain.Regeneration of the 17-acetyl side chain can be simply effected viaconventional oxidation means, for example, via oxidation with chromiumtrioxide in an organic solvent such as glacial acetic acid. Similarly incompounds containing a 17-oxo, this group can be protected by reductionto the corresponding carbinol (hydroxy) group. Thus, the 17-oxo groupcan be reduced to a 17β-OH, 17α-H moiety, from which, when desired, the17-oxo moiety can be regenerated by oxidation, as described above.Furthermore, a 20-hydroxy or 17β-hydroxy group, can itself be protectedby esterification, for example, with a lower alkanoic acid such asacetic acid, caproic acid, or the like; or by etherification withmoieties such as tetrahydropyranyl, benzyl, benzhydryl, trityl, allyl,or the like.

The 16α-17α or 17α,21-acetals and ketals above discussed can be formedby reacting 16α,17α-bis-hydroxy or 17α,21-bis-hydroxy starting materialswith an aldehyde or a ketone; preferably it is done by reacting a simpleacetal or ketal (i.e. a lower alkylene glycol acetal or ketal of asuitable aldehyde or ketone) with the moieties sought to be protected.

Suitable aldehydes and ketones include lower alkanals of at least twocarbon atoms, such as paraldehyde, propanal and hexanal; di(loweralkyl)ketones, such as acetone, diethylketone, dibutylketone,methylethylketone, and methylisobutylketone; cycloalkanones, such ascyclobutanone, cyclopentanone and cyclohexanone; cycloalkyl (loweralkanals), such as cyclopentylcarboxaldehyde andcyclohexylcarboxaldehyde; cycloalkyl lower alkyl ketones, such ascyclopentyl propyl ketone, cyclohexylmethyl ethyl ketone; dicycloalkylketones, such as dicyclopentyl ketone, dicyclohexyl ketone andcyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones,such as cyclohexyl p-chlorophenyl ketone, cyclopentyl o-methoxyphenylketone, cyclopentyl, o,p-dihydroxy-phenyl ketone and cyclohexyl m-tolylketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such ascyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic-loweralkyl ketones, such as cyclopentyl benzyl ketone and cyclohexylphenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkylketones, such as cyclopentylmethyl benzyl ketone; halo-lower alkanals,such as chloral hydrate, trifluoroacetaldehyde hemiacetal, andheptafluorobutanal ethyl hemiacetal; halo-lower alkanones, such as1,1,1-trifluoroacetone; monocyclic carbocyclic aromatic aldehydes, suchas benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde andp-fluorobenzaldehyde), lower alkoxy-benzaldehyes (e.g. o-anisaldehyde),di(lower alkoxy)benzaldehydes (e.g. veratraldehyde),hydroxybenzaldehydes (e.g. salicylaldehyde), lower alkyl benzaldehydes(e.g. m-tolualdehyde and p-ethylbenzaldehyde), di(loweralkyl)-benzaldehydes (e.g. o-p-dimethylbenzaldehyde); monocycliccarboxylic aromatic lower alkanals, such as phenylacetaldehyde,α-phenylpropionaldehyde, β-phenylpropionaldehyde, 4-phenylbutyraldehyde,and aromatically-substituted halo, lower alkoxy, hydroxy and lower alkylcyano derivatives thereof; monocyclic carbocyclic aromatic ketones, suchas acetophenone, α,α,α-trifluoroacetophenone, propiophenone,butyrophenone, valerophenone, halophenyl lower alkyl ketones (e.g.p-chloroacetophenone and p-chloropropiophenone); (lower alkoxy) phenyllower alkyl ketones (e.g. p-anisyl methyl ketone); di-(lower alkoxy)phenyl lower alkyl ketones; hydroxy-phenyl lower alkyl ketones; (loweralkyl)phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone); di(loweralkyl) phenyl lower alkyl ketones (o,p-xylyl methyl ketone;benzophenone, and mono- or bis-substituted halo, lower alkoxy, hydroxyand lower alkyl derivatives thereof; monocyclic carbocyclic aromaticlower alkanones, such as 1-phenyl-3-butanone and 1-phenyl-4-pentanone,and aromatically substituted derivatives thereof.

Especially suitable are those aldehydes or ketones which, with the16α,17α- or 17α,21-bis-hydroxy grouping form an acetal or ketal group ofthe formula ##EQU1## wherein P is individually selected from the groupconsisting of hydrogen and lower alkyl; Q is individually selected fromthe group consisting of lower alkyl and aryl; and P and Q taken togetherare lower alkylene.

The term "lower alkylene" comprehends polymethylene chains such astetramethylene and pentamethylene.

In discussing the various starting materials, intermediates andend-products of this invention, the various protecting groups discussedabove will not necessarily be specifically mentioned, but it should beunderstood that mention of any substituent comprehends the variousprotected forms thereof, unless specifically mentioned to the contrary.

In one embodiment of this invention, compounds of formula I through Vare prepared from 9β,10β-desA-androstan-5-ones or9β,10β-desA-pregnan-5-ones of the formula ##SPC6##

wherein X has the same meaning as above and D represents the carbon andhydrogen atoms necessary to complete the steroid D-ring, as well as theatoms in the substituents in the 16- and 17- positions, as defined informulae I-V above.

Thus, 9β,10α-androstanes of formula I can be prepared from9β,10β-desA-androstan-5-ones of the formula ##SPC7##

wherein R₁, R₂, R₃ and X have the same meaning as above.

Similarly, 9β,10α-androstanes of formula II can be prepared from9β,10β-desA-androstan-5-ones of formula VIII and 9β,10α-androstanes offormula III from 9β,10β-desA-androstan-5-ones of formula IX. ##SPC8##

wherein R₁, R₃ and X have the same meaning as above.

Moreover, 9β,10α-17β-pregnanes of formulae IV and V can be prepared from9β,10β-desA-pregnan-5-ones of formulae X and XI, respectively. ##SPC9##

wherein R'₃, R₅, R₆ and X have the same meaning as above.

The conversion of a 9β,10β-desA-compound of formula VI to a9β,10α-steroid of formulae I-V I, VIII→VII→I,VIII→II, IX→II, X→IV andXI→V) is effected by condensing the 9β,10β-desA-compound with a compoundselected from the group consisting of lower alkyl vinyl ketone (as wellas substitutes therefor such as 1-tertiary amino-3-butanone, 1-tertiaryamino-3-pentanone and quaternary ammonium salts thereof),1,3-dichlorobut-2-ene, 1,3-dichloropent-2-ene, 1Q-butan-3-one,1Q-butan-3-one lower alkylene ketal, 1Q-butan-3-ol, 1Q-butan-3-ol ether,esterified 1-Q-butan-3-ol, 1Q-pentan-3-one, 1Q-pentan-3-one loweralkylene ketal, 1Q-pentan-3-ol, 1-Q-pentan-3-ol ether or esterified1-Q-pentan-3-ol. Q is bromo, chloro or iodo, with the former two beingpreferred. Methyl vinyl ketone and 1-tertiary amino-3-butanone are thepreferred reagents, and the former is especially preferred. Prior to thecondensation it is desirable to protect the 20-keto group present incompounds of formulae X and XI, then it is not necessary to protect16α,17α or 21-hydroxy groups which are present, but groups protectingthese moieties can be retained through the condensation reaction.

The above indicated substitutes for lower alkyl vinyl ketones arecompounds wherein the vinyl moiety is replaced by a moiety of theformula ##EQU2## wherein each R is lower alkyl or taken together bothR's are lower alkylene, oxa-lower alkylene or aza-lower alkylene. Suchmoieties are, for example, dimethylamino, diethylamino, pyrrolidino,piperidino, morpholino, or the like. The quaternary ammonium saltsthereof are formed via the utilization of conventional quaternizingagents, for example, lower alkyl or phenyl-lower alkyl (especiallybenzyl) halides, mesylates or tosylates.

When a lower alkyl vinyl ketone or substitute therefor, 1-Q-butan-3-oneor 1-Q-pentan-3-one is used as the reaction partner for thecondensation, ring closure to ring A (containing a 3-oxo moiety) of thedesired 9β,10α -steroid of formulae I-V occurs simultaneously with thecondensation. However, when 1,3-dichlorobut-2-ene1,3-dichloropent-2-ene, 1-Q-butan-3-one lower alkylene ketal,1-Q-butan-3-ol, 1-Q-butan-3-ol ether, esterified 1-Q-butan-3-ol,1-Q-pentan-3-one lower alkylene ketal, 1-Q-pentan-3-ol, 1-Q-pentan-3-olether, or esterified 1-Q-pentan-3-ol is used as the reaction partner asubsequent step to generate the 3-oxo moiety is required. When1-Q-butan-3-ol or 1-Q-pentan-3-ol is used as the reaction partner, theoxo moiety can be generated by oxidation and for this purpose, it issuitable to use oxidation means known per se, for example, chromic acid,chromium trioxide in acetic acid or the like. When esterified oretherified 1-Q-butan-3-ol or esterified or etherified 1-Q-pentan-3-ol isused as the reaction partner, hydrolysis of the esterified or etherifiedhydroxy group should be effected prior to oxidation. Suitable esterforming moieties are, for example, carboxylic acids, e.g. lower alkanoicacid such as acetic acid, benzoic acid, and the like; and hydrolysis ofthe reaction products obtained by reacting such 1-Q-butan-3-ol or1-Q-pentan-3-ol esters is suitably conducted by alkaline hydrolysis,e.g., via the use of an aqueous alkali metal hydroxide such as aqueoussodium hydroxide. Suitable ethers are, for example, lower alkyl ethers,i.e. 3-methoxy, 3-ethoxy or the like; and these are suitably hydrolyzedby acid hydrolysis, e.g. via the use of an aqueous mineral acid such ashydrochloric acid, sulfuric acid or the like. When a 1-Q-butan-3-onelower alkylene ketal or a 1-Q-pentan-3-one lower alkylene ketal is usedas the reaction partner, mild acid hydrolysis of the ketal moietyresults in generation of the 3-oxo moiety. Finally, when1,3-dichlorobut-3-ene or 1,3-dichloropent-3-ene is used as the reactionpartner, the 3-oxo moiety can be generated by treatment with aconcentrated mineral acid, preferably a strong acid such as hydrochloricacid or sulfuric acid. It should be noted, the 1,3-dichlorobut-2-ene and1,3-dichloropent-2-ene may be used as reaction partners with compoundsof formulae X and XI, but not with the 17α-lower alkyl, alkenyl oralkynyl compounds of formulae VIII-IX. As will be apparent, when areaction partner based on butane (i.e. having a four carbon atomskeleton) is utilized a compound of formulae I-V wherein Y is hydrogenis obtained. Similarly, when a reaction partner based on pentane isutilized a compound of formulae I-V wherein Y is methyl is obtained.

In addition to the preparation of compounds of formulae I-V fromcompounds of formulae VI-XI by the use of the above mentioned reactionpartners, it is also possible by the procedures of this invention toprepare compounds of formulae I-V which, in the A-ring, in addition tocontaining an unsaturation between the 4-and 5-positions also contain anunsaturation between the 1- and 2-positions. Such 1,4-diene productscorresponding to the compounds of formulae I-V can be prepared fromcompounds of formulae VI-XI by condensation of the latter with areaction partner selected from the group consisting of ethinyl methylketone and ethinyl ethyl ketone (as well as substitutes therefor such asβ-tertiary amino-vinyl methyl or ethyl ketone, quaternary ammonium saltsthereof, and β-lower alkoxy-vinyl methyl or ethyl ketone). Condensationto prepare such a 1,4-diene product corresponding to the compounds offormulae I-V is effected under the same conditions as is thecondensation to prepare a compound of formulae I-V. The so-obtained1,4-dienes are useful in the same way as the correspondingly substituted4-ene-compounds of formulae I-V.

The condensation is suitably effected at, below or above roomtemperature. For example, at the reflux temperature of the reactionmedium or at ice temperature (0°C.) or below. Moreover, the condensationis suitably effected in an organic medium. Preferably the solvent is alower alkanol, such as methanol, isopropanol, tert-butanol, ethanol, oranother non-ketonic organic solvent, such as an ether, e.g. dioxane,diethyl ether, diisopropyl ether, aromatic hydrocarbon, e.g. benzene,toluene, xylene, organic acid, such as acetic acid, or the like. Loweralkanols are the preferred solvents. It is suitable to catalyze thecondensation, and this can be effected via use of a catalyst such as analkali metal lower alkoxide, for example sodium ethoxide, potassiumt-butoxide, sodium t-amylate, or the like, alkali metal hydroxide suchas sodium, lithium or potassium hydroxide, a quaternary ammoniumhydroxide, for example, a benzyl tri-lower alkyl ammonium hydroxide suchas benzyl trimethyl ammonium hydroxide, para-toluene sulfonic acid, orthe like.

When using a substitute for methyl or ethyl vinyl ketone, or for methylor ethyl ethinyl ketone, the condensation should be effected underalkaline conditions. As indicated above, among such substitutes are1-tertiary amino-3-butanone, 1-tertiary amino-3-pentanone and β-tertiaryamino-vinyl methyl or ethyl ketone. Preferred tertiary amino groups aredilower alkylamino groups such as dimethylamino, diethylamino,pyrrolidino, piperidino, morpholino, or the like. Preferred quaternaryammonium salts of such tertiary amino groups are, for example, thoseformed from lower alkyl halides such as methyl iodide. An exemplaryβ-lower alkoxy vinyl methyl or ethyl ketone is β-methoxyvinyl ethylketone.

One aspect of this invention is the hydrogenation ofdesA-androst-9-en-5-ones or desA-pregn-9-en-5-ones to9β,10β-desA-androstan-5-ones of formulae VII-IX or to9β,10β-desA-pregnan-5-ones of formulae X-XI. Thus,9β,10β-desA-androstan-5-ones of formula VII can be prepared viahydrogenation of desA-androst-9-en-5-ones of the formulae ##SPC10##

wherein R₁, R₂, R₃ and X have the same meaning as above.

Also, 9β,10β-desA-pregnan-5-ones of formulae X and XI can be prepared byhydrogenation of desA-pregn-9-en-5-ones of the formulae ##SPC11##

wherein R'₃, R₅, R₆ and X have the same meaning as above.

Prior to hydrogenation, the C-20 keto group in compounds of formulae XVand XVI or C-17 keto group in compounds of formula XII should beprotected either by conversion to the corresponding carbinol or byketalization as described above. The hydrogenation can, however, beeffected without protecting such keto groups.

Moreover, it should be noted that the hydrogenation, besides inserting ahydrogen atom in each of the 9- and 10-positions, can alsosimultaneously effect hydrogenation of other groups in the molecule. Forexample, the C-20-keto group can be hydrogenated to the correspondingcarbinol or the C-17 lower alkenyl group in compounds of formula XIII orthe C-17 lower alkynyl group in compounds of formula XIV can behydrogenated to the corresponding C-17-lower alkyl compounds. Compoundsof formulae VIII and IX can, in turn, be prepared from compounds offormula VII wherein R₁ and R₂ together are oxo via reaction with a loweralkenyl or lower alkynyl Grignard reagent, with prior protection of the5-keto group, for example, by forming 5-ketals without concurrentblocking of the 17-keto group. In the same manner compounds of formulaeXIII and XIV can be formed from compounds of formula XII wherein R₁ andR₂ taken together are oxo.

The hydrogenation of desA-androst-9-en-5-ones of formulae XII-XIV and ofdesA-pregn-9-en-5-ones of formulae XV-XVI is one of the main features ofthis invention. It is effected by catalytic hydrogenation, suitablyusing a precious metal catalyst. Suitable precious metal catalysts arepalladium, platinum, ruthenium, and rhodium, the latter two beingespecially preferred. It is particularly advantageous to use rhodium,for example, rhodium on charcoal (or carbon powder, carbon black, or thelike) or rhodium on alumina. In contrast to what would be expected, ithas been found that such a catalytic hydrogenation of a compound offormulae XII-XVI gives a substantial yield of a compound of formulaeVI-XI. In fact, it has been found that such catalytic hydrogenationgives a major proportion of a compound of the formulae VI-XI. Thiscatalytic hydrogenation is suitably effected in an inert organicsolvent, for example, a lower alkanol such as methanol or ethanol, anether such as dioxane or diglyme, a hydrocarbon such as cyclohexane,hexane, or the like. Lower alkanols are preferred solvents. Moreover, itis suitably conducted in the presence of an acidic or basic catalyst,for example, an alkali metal or alkaline earth metal hydroxide such assodium hydroxide or the like, or a mineral acid, for example, ahydrohalic acid, such as hydrochloric acid, or the like, or an organicacid such as a lower alkanoic acid, for example, acetic acid. Thereaction can be conducted at, above or below room temperature, forexample, from about -5°C. to about 100°C. However, it is preferablyconducted at a temperature between about 0°C. and about 35°C.

As described above, the desA-androst-9-ene-5-ones ordesA-17β-pregn-9-en-5-ones of formulae XII-XVI can be prepared fromnatural steroids by a variety of methods. Thus, in one embodiment ofthis invention said desA-androst -9-en-5-ones ordesA-17β-pregn-9-en-5-ones can be prepared from steroids of the3-oxo-androst-4-ene or 3-oxo-17β-pregn-4-ene series by a reactionsequence which involves as a first step an oxidative ring opening ofring A of the natural steroid. For this oxidative ring opening there canbe used as starting materials, natural steroids of the3-oxo-androst-4-ene or 3-oxo-17β-pregn-4-ene series of the formula:##SPC12##

wherein X' is a substituent in the 6-position selected from the groupconsisting of hydrogen, lower alkyl, lower alkylthio and loweralkanoylthio or a substituent in the 7-position selected from the groupconsisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthioand halogen, and Z represents the carbon and hydrogen atoms necessary tocomplete the steroid D-ring, as well as the atoms in the substituents inthe 16- and 17-positions as defined in formulae I, IV, and V above.

The oxidative ring opening of a natural steroid of formula XVII yields a5-oxo-3,5-seco-A-norandrostan-3-oic acid or a5-oxo-3,5-seco-A-norpregnan-3-oic acid of the formula ##SPC13##

wherein X' and Z have the same meaning as above. The oxidative ringopening of the compound of formula XVII can be performed by a variety ofmethods. In a preferred embodiment it is effected by ozonolysis. Theozonolysis is suitably carried out in an organic solvent, for example,acetic acid, ethyl acetate, methanol, chloroform, methylene chloride, orthe like, or a mixture of two or more of such solvents such as ethylacetate/acetic acid, ethyl acetate/methylene chloride, or the like.Moreover, the ozonolysis is advantageously conducted at below roomtemperature. Thus, it is preferably conducted at a temperature betweenabout -70°C. and about 25°C. The resulting ozonides can be decomposed byconventional means, for example, by treatment with water, hydrogenperoxide in water, acetic acid or ethyl acetate, or the like. Theoxidative ring opening of a compound of formula XVII to a compound offormula XVIII can also be effected by other oxidation means, forexample, by treatment with hydrogen peroxide. It should be noted that anoxidative ring opening by either ozonolysis or by treatment withhydrogen peroxide, does not require protection of any of thesubstituents at C-16 or C-17. However, as stated above, it may bedesirable to protect these substituents against some subsequent reactionin the total reaction sequence being practiced. On the other hand, theoxidative ring opening can also be effected by oxidation with chromiumtrioxide or via treatment with sodium periodate and potassiumpermanganate in potassium carbonate solution and if these oxidationmeans are used, it is necessary to protect any secondary hydroxy groupswhich might be present such as a 16,17β- or 21-hydroxy group;preferably, for the purpose of this reaction, with non-aromaticprotecting groups.

Following the oxidative ring opening of the A-ring, the so-obtained5-oxo-3,5-seco-A-norandrostan-3-oic acid or5-oxo-3,5-seco-A-norpregnan-3-oic acid of formula XVIII is convertedinto a mixture of a 10α-desA-androstan-5-one and a10β-desA-androstan-5-one one or a mixture of a 10α-desA-pregnan-5-oneand a 10β-desA-pregnan-5-one as illustrated below: ##SPC14##

wherein in formulae XIX and XX, X' and Z have the same meaning as above.

The compounds of formula XIX are 10α-desA-androstan-5-ones or10α-desA-pregnan-5ones, depending on the meaning of Z, and the compoundsof formula XX are 10β-desA-androstan-5-ones or 10β-desA-pregnan-5-ones.The conversion of a compound of formula XVIII into the compounds offormula XIX and XX is effected by pyrolysis. In effecting the pyrolysis,it is desirable to convert the 3-oic acid of formula XVIII into acorresponding metal salt, for example, an alkali metal salt such as thesodium or lithium salt. This conversion to a metal salt can be effectedprior to pyrolysis, e.g., by treating the acid sodium hydroxide or insitu during the course of the pyrolysis, e.g., by fusing the 3-oic acidwith a mixture of sodium acetate and potassium acetate. The pyrolysiscan be conducted at atmospheric pressure or in a vacuum. One preferableembodiment is to conduct the pyrolysis in a vacuum, at a temperaturefrom about 200°C. to about 350°C. in the presence of a proton acceptor,e.g. an alkali metal or alkaline earth metal salt of a weak organicacid, for example, potassium acetate, sodium acetate, sodiumphenyl-acetate, sodium bicarbonate, or the like; especially preferred isa vacuum of from about 0.001 to about 0.5 mm. Hg. Accordingly, it isadvantageous to conduct the pyrolysis under alkaline conditions, i.e. ata pH greater than 7. The pyrolysis can be effected in solution or byfusion. An especially preferred method of effecting the pyrolysis is byfusion of an alkali metal salt of a weak acid, for example, an organiccarboxylic acid such as a lower alkanoic acid or a phenyl-lower alkanoicacid such as phenyl-acetic acid. Another method of effecting thepyrolysis is to heat, preferably at atmospheric pressure, a solution ofan alkali metal salt, such as the sodium or lithium salt, of a 3-oicacid of formula XVIII in a basic organic solvent. The basic organicsolvent should, of course, be one which is in the liquid state at thetemperature at which the pyrolysis is effected. Thus, the pyrolysis canbe effected at a temperature up to the boiling point of the basicorganic solvent being used. Suitable basic organic solvents are, forexample, nitrogen containing organic solvents such as piperidine,pyridine, isoquinoline, quinoline, triethanolamine, or the like. Whenutilizing this approach using a basic organic solvent it is suitable toheat to temperature between about 200°C. and about 300°C., andpreferably between about 230°C. and about 260°C. A preferred basicorganic solvent for the pyrolysis of a salt of a compound of formulaXVIII to compounds of formulae XIX and XX is quinoline. If a basicorganic solvent is used which boils substantially below 200°C. atatmospheric pressure, it is suitable to conduct the pyrolysis in asealed tube or an autoclave.

In another aspect, compounds of formula XIX can be prepared fromcompounds of the formula ##SPC15##

wherein X' and Z have the same meaning as above.

The compounds of formula XIX can be prepared from compounds of formulaXIX A in the same manner that compounds of formula XIX are prepared fromcompounds of formula XVII, i.e. by oxidative ring opening of the A-ringof a compound XIX A followed by elimination of the residue of theA-ring, to yield a compound of formula XIX. The oxidative ring openingof the compound of XIX A can be performed by ozonolysis as describedabove for the conversion of a compound of formula XVII to a compound offormula XVIII. Such ozonolysis of a compound of formula XIX A yields acompound of the formula ##SPC16##

wherein X' and Z have the same meaning as above, and A is carboxy orformyl.

A compound of formula XIX B can then be converted to a compound offormula XIX. This removal of the residue of the A-ring, i.e.decarboxylation and deformylation, can be effected by heating in anacidic or basic medium. It is preferred to heat to the refluxtemperature of the medium which is preferably an inert organic solventsuch as a lower alkanol, e.g. ethanol, dioxane, ether or the like. Thedecarboxylation and deformylation yields mainly a compound of formulaXIX, but also a minor yield of the corresponding 10β-isomer of formulaXX.

Compounds of formula XIX can also be formed from a compound of formulaXVIII via the formation of an enol-lactone of a compound of formulaXVIII, i.e. via the formation of a 4-oxo-androst-5-en-3-one or a4-oxo-pregn-5-en-3-one of the formula: ##SPC17##

wherein X' and Z have the same meaning as above,

which can then be reacted with a Grignard reagent, such as phenylmagnesium bromide or phenyl lithium, to form the resulting aldol of, forexample, the formula ##SPC18##

wherein X' and Z have the same meaning as above,

which, upon treatment with an alkali metal hydroxide, such as potassiumhydorxide, at an elevated temperature, for example, from about 200°C. toabout 240°C., is converted to the corresponding 10α-desA-androstan-5-oneor 10α-desA-pregnan-5-one of formula XIX.

It should be noted that though the pyrolysis of a compound of formulaXVIII yields both the 10β-compounds of formula XX and the 10α-compoundsof formula XIX, and though either of these isomers can be used in thesubsequent halogenation and dehydro-halogenation steps of this reactionsequence, it is sometimes preferable to convert the 10β-compound offormula XX into the corresponding 10α-compound of formula XIX. Thisconversion can be effected by treating a 10β-desA-androstan-5-one or10β-desA-pregnan-5-one of formula XX with any base capable of producinga carbanion; for example, it is suitable to use an alkali metal loweralkoxide in an organic solvent such as a lower alkanol, for example,sodium ethoxide in an ethanol solution or sodium methoxide in a methanolsolution.

The above-discussed conversion via the alkali metal salt and pyrolysisof compounds of formula XVIII to compounds of formulas XIX and XX can beeffected without protection of any of the substituents which might bepresent at C-16 or C-17. However, if it is desired for either precedingor succeeding reaction steps of the total reaction sequence, theconversion of a compound of formula XVIII to compounds of formulas XIXand XX can be effected with protecting groups present on substituents inthe C-16 or C-17 position.

As stated above, the 10α-desA-androstan-5-ones or10α-desA-pregnan-5-ones of formula XIX or the 10β-desA-androstan-5-onesof 10β-desA-pregnan-5-ones of formula XX can be converted via a two-stepsequence of halogenation and dehydrohalogenation into the desiredstarting material desA-androst-9-en-5-one or desA-pregn-9-en-5-one offormulas XII, XV, and XVI.

In a preferred embodiment a 10α-desA-androstan-5-one or a10α-desA-pregnan-5-one of formula XIX is subjected to the two-stepsequence of halogenation and dehydrohalogenation. Halogenation of acompound of formula XIX or a compound of formula XX yields a mixture ofcorresponding halogenated compounds including one of the formula##SPC19##

wherein X' and Z have the same meaning as above, and Hal is a halogenatom (preferably Br or Cl).

Dehydrohalogenation of a compound of formula XXIII then yields a desiredstarting material of formulas XII, XV and XVI. Keto groups except forthe 5-keto group, may require protection prior to the halogenation. Inthe case of compounds of formulas XIX and XX containing the C-17dihydroxyacetone side chain, represented in formula V wherein R₆ ishydroxy, this protection can be effected by formation of the 17α,20;20,21-bis-methylenedioxy derivative. In other cases wherein a C-17oxo or C-20 oxo group is present, protection can be effected byreduction to the corresponding carbinol directly prior to thehalogenation step or prior to some other step in the reaction sequenceleading to the compounds of formulas XIX and XX.

The halogenation can be effected with halogenating agents such asbromine, sulfuryl chloride, or the like. Bromination is especiallypreferred. The bromination is suitably effected by treatment withbromine at room temperature or below, preferably at ice temperature orbelow. Suitably it is conducted in an organic medium; for example, anorganic acid such as acetic acid; an ether such as an anhydrous ether,dioxane, tetrahydrofuran; a chlorinated organic solvent such asmethylene chloride, chloroform, carbon tetrachloride; or the like; withthe addition of hydrogen bromide as a catalyst. When effectinghalogenation with sulfuryl chloride, it is suitable to use the same typeof organic medium as when brominating; and suitable catalysts are, forexample, acetic acid, benzoyl peroxide, or the like.

The subsequent dehydrohalogenation of a compound of formula XXIII ispreferably conducted under mild dehydrohalogenating conditions; forexample, by the use of an alkali metal carbonate (e.g. lithiumcarbonate) or an alkali metal halogenide (e.g. a lithium halide) in anorganic solvent such as a di-lower alkyl-formamide, or with an organicbase such as collidine, pyridine, or the like. The dehydrohalogenationis advantageously conducted at slightly elevated temperatures, forexample, from about 50°C. to about 150°C., preferably from about 80°C.to about 120°C.

Separation of the desired product desA-androst-9-en-5-one ordesA-pregn-9-en-5-one of formulas XII, XV and XVI can be effected byconventional means. As indicated above the halogenation procedure mayresult in halogenated by-products in addition to the desiredintermediate of formula XXIII. Accordingly, the separation is preferablyeffected after first subjecting the reaction mixture to dehalogenatingconditions in order to dehalogenate the halogenated by-products formedby the halogenation procedure, but not dehalogenated by thedehydrohalogenation. Following such dehalogenation the reaction mixturecan then easily be separated by conventional means, for example, bycolumn chromatography, to yield the desired compound of formulas XII,XV, XVI. An examplary dehalogenation means is treatment with zinc andsodium acetate in an acetic acid solution at an elevated temperature,for example, about 80°C.

In the case of compounds of formulas XIX or XX which contain a halogenatom on a carbon atom directly adjacent to a keto group, it ispreferable to protect such a halogen atom against dehalogenation priorto subjecting the compound of formulas XIX or XX to the two stepsequence of halogenation and dehydrohalogenation of this embodiment.Such a grouping, containing a halogen atom on a carbon atom directlyadjacent to a keto group, is illustrated in a compound of formulas IV orV wherein R₅ or R₆ is halogen. Thus, if 10α- or 10β-desA-pregnan-5-oneof formulas XIX or XX containing a 17α- or 21-halo substituent is to besubjected to the halogenation-dehydrohalogenation sequence it isdesirable to first effect protection of the 17α- or 21-halo substituent.This protection can be effected, for example, by ketalization of the20-oxo group.

As stated above, the desired desA-androst-9-en-5-ones ordesA-pregn-9-en-5-ones starting materials can also be prepared fromsteroids of the 3-oxo-androst-4-ene or 3-oxo-17β-pregn-4-ene seriescontaining an 11-hydroxy substituent. In one embodiment an 11-hydroxysteroid of the formula ##SPC20##

wherein X and Z have the same meaning as above,

is reacted with an acid or a reactive derivative thereof to form aleaving group in the 11-position. By reactive derivative is meant, forexample, a halide, e.g. a chloride, an anhydride, or the like. Thougheither 11β- or 11α-hydroxy starting materials can be used, it ispreferable to utilize α-hydroxy compounds of formula XXIV as startingmaterials. Prior to the esterification reaction, it is preferable toprotect hydroxy groups present in the C-16, C-17, or C-21 position.Suitable acids for the esterification of the 11-hydroxy group, which canbe used to form a leaving group in the 11-position are inorganic acidssuch as phosphoric acid, organic carboxylic acids such as anthraquinoneβ-carboxylic acid or organic sulfonic acids, for example,toluene-sulfonic acids, especially p-toluene sulfonic acid, loweralkyl-sulfonic acids such as methane-sulfonic acid andnitrophenyl-sulfonic acids, especially p-nitrophenylsulfonic acid.Especially preferred as the leaving group in the 11-position is a loweralkylsulfonyloxy group such as the mesoxy group. However, when it isdesired to react a compound of formula XXIV with a sulfonyloxy formingmoiety, then a compound of formula XXIV having an 11α-configurationshould be used as a starting material. The above describedesterification of 11-hydroxy steroid starting materials of formula XXIVyields compounds of the formula ##SPC21##

wherein X and Z have the same meaning as above, and LO represents theleaving group.

In the next step of this reaction sequence, the so-formed 11-(esterifiedhydroxy)-compound of formula XXV is subjected to an oxidative ringopening of the A-ring to yield the corresponding 11-(esterifiedhydroxy)-5-oxo-3,5-seco-A-norandrostan-3-oic acid or 11-(esterifiedhydroxy)-5-oxo-3,5-seco-A-norpregnan-3-oic acid of the formula ##SPC22##

wherein X, Z and LO have the same meaning as above.

The oxidative ring opening of the A-ring of a compound of formula XXV toa compound of formula XXVI can be effected by ozonolysis as describedabove for the oxidative ring opening of the A-ring of a compound offormula XVII to a compound of formula XVIII. Pyrolysis of the so-formedcompound of formula XXVI under the conditions described above for thepyrolysis of a compound of formula XVIII to compounds of the formulasXIX and XX directly yields the desired desA-androst-9-en-5-one ordesA-pregn-9-en-5-one of formulas XII, XV, XVI. Thus, pyrolysis of acompound of formula XXVI directly results in elimination of the leavinggroup in the 11-position as well as a splitting off of the residue ofring A attached to the 10-position. This procedure of starting from an11-hydroxy steroid (preferably 11α-hydroxy) of formula XXIV andproceeding through intermediates of formulas XXV and XXVI to compoundsof formulas XII, XV, XVI, represents a particularly elegant procedurefor preparing the latter compounds. An especially preferred method ofeffecting the pyrolysis of a salt of a 3-oic acid of formula XXVI is themethod described above wherein the salt of the 3-oic acid is heated in aliquid basic organic solvent. Especially preferred solvents for thepyrolysis of a salt of a compound of formula XXVI are triethanolamineand quinoline.

As indicated in the foregoing paragraph the pyrolysis of a salt of acompound of formula XXVI involves two separate chemical attacks; onebeing the elimination of the 11-leaving group and the other being thesplitting off of the A-ring residue. Instead of effecting these twoattacks simultaneously, as described above, it is also possible toeffect them sequentially by just prior to formation of the salt,effecting elimination of the leaving group of the compound of formulaXXVI. This elimination yields a Δ⁹(11) -seco acid of the formula##SPC23##

wherein X and Z have the same meaning as above.

The elimination can be effected by any conventional elimination means.It is suitably conducted under alkaline conditions in an anhydrousorganic solvent. Preferably, it is effected by heating, i.e. at atemperature between about room temperature and the reflux temperature ofthe reaction mixture. Thus, treatment of a compound of formula XXVI witheither an inorganic or organic acid or base results in the formation ofthe desired compound of formula XXVIA. Preferably a weak base is used,for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid)with an alkali metal or an alkaline earth metal, for example, sodiumacetate, potassium acetate, of the like. As indicated, the eliminationis suitably conducted in an anhydrous organic solvent; suitable aresolvents such as dilower alkyl-formamides, e.g. dimethylformamide, loweralkanoic acids, e.g. acetic acid, or the like. When a proton acceptingsolvent, such as dimethylformamide, is used, it itself can serve as thebase for the purpose of this elimination reaction; i.e. if the solventis basic then the elimination can be conducted without the addition of aseparate basic material. Similarly, if the solvent is acidic, then theelimination can be conducted without the addition of a separate acidicmaterial.

After the elimination is effected the Δ⁹(11) -seco acid product offormula XXVIA can then be converted to a salt, for example, an alkalimetal salt, and the so-formed salt pyrolyzed according to the conditionsdescribed above for the pyrolysis of a compound of formula XXVI tocompounds of formulas XII, XV and XVI.

After the above-described 11-leaving group elimination and A-ringresidue splitting, conducted either simultaneously or sequentially, thedesired desA-9-en-5-one -compounds of formulas XII, XV and XVI can beisolated by conventional means. However, is has been found particularlysuitable with compounds of formulas XV and XVI to isolate by forming thedisemicarbazone of the pyrolysis product and then regenerating therefromthe desired 5,20-dione of formulas XV or XVI, or if the 20-oxo group hasbeen protected, for example, by reduction to a 20-hydroxy moiety, byforming the semicarbazone at the 5-position and then regeneratingtherefrom the desired 5-one compound.

In yet another embodiment of this invention starting material 11-hydroxysteroids of formula XXIV can be directly subjected to an oxidative ringopening of the A-ring by ozonolysis or treatment with hydroxideperoxide, as described above for the oxidative ring opening of theA-ring of a compound of formula XVII to a compound of formula XVIII.This oxidative ring opening of the A-ring of a compound of formula XXIVyeilds an 11-hydroxy-5-oxo-3,5-seco-A-norandrostan-5-oic acid3,11-lactone or an 11-hydroxy-3-oxo-3,5-seco-A-norpregnan-3-oic acid3,11-lactone of the formula ##SPC24##

wherein X and Z have the same meaning as above.

Treatment of the 3,11-lactone of formula XXVII with an alkali metalhydroxide such as sodium hydroxide gives the salt of the same keto acid.Without isolation, this salt can then be subjected to pyrolysis yieldinga mixture of an 11-hydroxy-10αdesA-androstan-5-one and an11-hydroxy-10β-desA-androstan-5-one or a mixture of an11-hydroxy-10α-desA-pregnan-5-one and an11-hydroxy-10β-desA-pregnan-5-one, as illustrated below: ##SPC25##

wherein in formulas XXVIII and XXIX, XX and Z have the same meaning asabove.

This pyrolysis of an alkali metal salt derived from a compound offormula XXVII can be effected under the same conditions as describedabove for the pyrolysis of a compound of formula XVIII to compounds ofthe formulae XIX and XX. Though either the 10β-compound of formulaXXVIII or the 10α-compound of formula XXIX can be subjected to thesubsequent steps of this reaction sequence, it is suitable to utilizethe 10β-compound of formula XXVIII. Conversion of the 10α-compound offormula XXIX to the 10β-compound of formula XXVIII can be effected underthe same conditions as described above for the conversion of thecompound of formula XX to a compound of formula XIX.

In the next step of this reaction sequence, the 11-hydroxy compound offormula XXVIII or of formula XXIX can be subjected to esterificationwhereby to convert the 11-hydroxy group to a leaving group in the11-position. This esterification can be effected with the same acids oracid derivatives and in the same manner as described above for theesterification of a compound of formula XXIV to a compound of formulaXXV. As in that instance, it is also preferred in the present instanceto form a mesoxy leaving group in the 11-position, though, of course,other leaving groups as described above are useful for the instantpurpose. There is thus obtained a compound of the formula ##SPC26##

wherein X, Z and LO have the same meanings as above.

The leaving group can then be eliminated from the 11-position of acompound of formula XXX resulting in a direct formation of adesA-androst-9-en-5-one or a desA-pregn-9-en-5-one of formulae XII, XV,XVI. This elimination can be effected by any conventional eliminationmeans. It is suitably conducted under alkaline conditions in ananhydrous organic solvent. Preferably, it is effected by heating, i.e.at a temperature between about room temperature and the refluxtemperature of the reaction mixture. Thus, treatment of a compound offormula XXX with either an inorganic or organic base results in theformation of the desired compound of formulae XII, XV, XVI. Preferably aweak base is used, for example, a salt of a carboxylic acid (e.g. alower alkanoic acid) with an alkali metal or an alkaline earth metal,for example, sodium acetate, potassium acetate, or the like. Asindicated, the elimination is suitably conducted in an anhydrous organicsolvent; suitable are solvents such as dilower alkyl-formamides, e.g.dimethyl formamide, lower alkanoic acids, e.g. acetic acid, or the like.When a proton accepting solvent, such as dimethyl formamide, is used, ititself can serve as the base for the purpose of this eliminationreaction; i.e. if the solvent is basic then the elimination can beconducted without the addition of a separate basic material.

In another aspect, compounds of Formula XXX can be prepared fromcompounds of the formula ##SPC27##

wherein X, Z and LO have the same meanings as above.

The compounds of formula XXXA can be prepared from corresponding11-hydroxy compounds by esterification as described above for thepreparation of compounds of formula XXV from compounds of formula XXIV.The compounds of formula XXX can be prepared from compounds of formulaXXXA in the same member that compounds of formula XXX are prepared fromcompounds of formula XXV, i.e. by oxidative ring opening of the A-ringof a compound of formula XXXA followed by elimination of the residue ofthe A-ring to yield a compound of formula XXX. The oxidative ringopening of the compounds of formula XXXA can be performed by ozonolysisas described above for conversion of a compound of formula XXV to acompound of formula XXVI. Such ozonolysis of a compound of formula XXXAyields a compound of the formula ##SPC28##

wherein X, Z and LO have the same meaning as above.

A compound of formula XXXB can then be converted to a compound offormula XXX. This removal of the residue of the A-ring, i.e.decarboxylation, can be effected as described above for the conversionof a compound of formula XIXB to a compound of formula XIX.

The compounds of formulae I-V preparable by the methods of thisinvention are not only pharmaceutically useful compounds as describedabove, but also are themselves useful as intermediates for other 9β,10α-steroids; for example, compounds wherein X is hydrogen or loweralkyl can be modified so as to introduce unsaturation between C-6 andC-7. This can be effected by dehydrogenation means, for example, byhalogenation followed by dehydrohalogenation or by means of2,3-dichloro-5,6-dicyanobenzoquinone, according to known methods. Thus,for example, a 9β, 10α-progesterone of formula IV wherein X is hydrogenor lower alkyl can be converted to a 9β,10α-pregna-4,6-dien-3,20 -dione.

A further embodiment of this invention comprises the preparation of9β,10α-steroids of formulae I-V containing an 11-hydroxy substituent.This can be effected by utilizing an 11-hydroxy-10β-desA-androstan-5-oneor 11-hydroxy-10α-desA-pregnan-5-one of formula XXIX or an11-hydroxy-10β-desA-androstan-5-one or 11-hydroxy-10β-desA-pregnan-5-oneof formula XXVIII as the starting materials. It is preferred in thisembodiment to use the 10β-isomers of formula XXVIII as startingmaterials. As a first step in this the 11-hydroxy group of the compoundof formulae XXVIII or XXIX should be protected. This is suitablyeffected by esterification, preferably with a carboxylic acid, forexample, a lower alkanoic acid such as acetic acid, benzoic acid, or thelike. Conversion of the so-obtained 11-esterified hydroxy compound thenyields an 11-(esterified hydroxy)-desA-androst-9-en-5-one (i.e. acompound of formula XII containing an 11-esterified hydroxy moiety) oran 11-esterified hydroxy-desA-pregn-9-en-5-one (i.e. a compound offormulae XV-XVI containing an 11α-esterified hydroxy moiety). Thisconversion can be effected by halogenation followed bydehydrohalogenation, as described above for the conversion of a compoundof formulae XIX or XX to a compound of formulae XII, XV or XVI.Catalytic hydrogenation of the so-obtained compound of the formula##SPC29##

wherein X' and Z have the same meaning as above, and EO is an esterifiedhydroxy group as described above in this paragraph,

yields an 11 -esterified hydroxy-desA-9β, 10β-androstan-5-one or 11-esterified hydroxy-desA-9β,10β-pregnan-5-one, of the formula ##SPC30##

wherein X', Z and EO have the same meaning as above.

This hydrogenation can be conducted in the same manner as describedabove for the hydrogenation of a compound of formulae XII-XVI to acompound of formulae VII, X, XI. Also, compounds of formula XXXIIcontaining a 17-oxo moiety can be converted to a corresponding compoundcontaining a 17β-hydroxy, 17α-lower alkenyl or lower alkynyl moiety bythe methods described above. Also, compounds of formula XXXII can behydrolyzed to yield corresponding 11-hydroxy compounds of formula XXXII,i.e. wherein EO is hydroxy.

Condensation of the so-obtained compound of formula XXXII or thecorresponding 17β-hydroxy, 17α-lower alkenyl or lower alkynyl compound(i.e. a compound of formula VI containing a free or 11-esterifiedhydroxy group) then yields the desired end-product 9β, 10α-steroid offormulae I-V containing an 11-hydroxy group. Such condensation can beeffected as described above for the preparation of a compound offormulae I-V from a compound of formulae VI-XI. The so-obtained 9β,10α-steroids containing an 11-esterified hydroxy group can be hydrolyzedto the corresponding compounds containing an 11-hydroxy group, whichlatter compounds are themselves useful as intermediates, for example,the 11-hydroxy group can be oxidized by methods known per se to yieldcorresponding 11-oxo steroids analogous to compounds of formulas I-V.

The pharmaceutically useful compounds prepared by the methods of thisinvention can be administered internally, for example, orally orparenterally, with dosage adjusted to individual requirements. They canbe administered in conventional pharmaceutical forms, e.g. capsules,tablets, suspensions, solutions, or the like.

The following examples are illustrative but not limitative of thisinvention. All temperatures are in degrees Centigrade. The Florisiladsorbent used infra is a synthetic magnesia-silica gel available fromthe Floridin Company, P. O. Box 989, Tallahassee, Flor. (cf. p. 1590,Merck Index, 7th Edition, 1960). 100-200 mesh material was used. Themoiety designated by tetrahydropyranyloxy is tetrahydro-2-pyranyloxy.When it is stated that a precedure is effected in the cold, it should beunderstood that it is commenced at 0°C. Throughout this application whencompounds of the pregnane series are referred to it should be understoodthat it is compounds of the 17β-pregnane series that are being referredto, unless specifically indicated to the contrary, and whether or notthe compound of the pregnane series is specifically indicated as of the17β-series.

EXAMPLE 1

A solution of 3.2 g. of 17α-ethyltestosterone in 50 ml. methylenechloride and 25 ml. ethyl acetate was ozonized at -70° (acetone-dry icebath) until the solution was blue in color. After oxygen was passedthrough, the solution was evaporated at room temperature in vacuo. Thesyrupy residue was then dissolved in 100 ml. of glacial acetic acid, andafter addition of 5 ml. of 30 per cent hydrogen peroxide, left for 24hours at 0°-5°. Following this time, it was evaporated to dryness,dissolved in 1500 ml. ether, and extracted with 2N sodium carbonatesolution. The alkaline extract was poured in ice cold hydrochloric acid.The resultant crystalline17α-ethyl-17β-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid wasfiltered, washed with water and dried. Upon being recrystallized fromacetone, it melted at 196°-197°.

EXAMPLE 2

A solution of 1.5 g. of17α-ethyl-17β-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid in 100ml. of methanol was titrated with 2N sodium methoxide to the reddishcolor of phenolphthaleine, and then evaporated to dryness in vacuo,giving as the residue, the sodium salt of17α-ethyl-17β-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid. 5 g. ofsodium-phenylacetate was added to the residue, and the mixture pyrolyzedin vacuo (<0.1 mm) at 285°-295°, for 2.5 hours. The sublimate wasdissolved in acetone, filtered and the filtrate concentrated in vacuo.The resultant syrupy residue was chromatographed on a 60 g. Florisil(adsorbent) column. The fractions eluted with benzene and 0.5 per centethylacetate in benzene were combined and gave17α-ethyl-17β-hydroxy-10α-desA-androstan-5-one, m.p. 94°-95° afterrecrystallization from petroleum ether. The fractions eluted with 2 percent and 5 per cent ethylacetate in benzene were combined and gave17α-ethyl-17β-hydroxy-10β-desA-androstan-5-one, m.p. 185°-185.5°,recrystallizations two recrystallization from petroleum ether.

EXAMPLE 2a

To a solution of 100 mg. of17α-ethyl-17β-hydroxy-10β-desA-androstan-5-one in 10 ml. of absoluteethanol was added one equivalent of sodium ethoxide dissolved in 5 ml.of absolute ethanol. This reaction mixture was maintained at roomtemperature overnight, then acidified with glacial acetic acid, pouredin water and extracted with methylene chloride. The extract was washedwith water, dried over anhydrous sodium sulfate and concentrated invacuo. Thin layer chromatography showed the product to be17α-ethyl-17β-hydroxy-10α-desA-androstan-5-one. It was obtainedcrystalline from petroleum ether-ether and melted at 89°-95°.

EXAMPLE 3

1.13 g. of 17α-ethyl-17β-hydroxy-10α-desA-androstan-5-one was dissolvedin 120 ml. of anhydrous ether (or 1.13 g. of 10β-isomer was dissolved in300 ml. of anhydrous ether), and after cooling in a salt-ice bath,several drops of 30 per cent hydrobromic acid in acetic acid were added.This was followed by the dropwise addition during five minutes of 0.684g. of bromine dissolved in 2 ml. of acetic acid. This addition wassynchronized with the decoloration rate of the reaction mixture.Immediately after this, 5 ml. of a saturated solution of sodiumbisulfite and 5 ml. of 2N sodium carbonate solution were added. Themixture was then transferred into a separatory funnel, 500 ml. of etheradded, shaken and separated. The ether part was washed with water, driedand evaporated. The resultant bromides were dissolved in 100 ml. ofdimethylformamide, and after addition of 3 g. of lithium carbonate, thesolution was heated at 100° for 45 minutes. After cooling, it was pouredinto one liter of ether, washed with water, 1N hydrochloric acid, 2Nsodium carbonate, water, dried and evaporated. The residue was dissolvedin 40 ml. of glacial acetic acid, 1.2 g. of sodium acetate and 1.2 g. ofzinc powder added, and the so-formed mixture heated 10 minutes at 80°.It was then poured into one liter of ethylacetate and the resultantsolution washed with saturated sodium bicarbonate, then with water,dried and evaporated. The residue was chromatographed on Florisil(adsorbent)column. The fraction with benzene and 1/2 per centethylacetate in benzene gave regenerated starting material. Fractionswith 1 and 2 per cent ethylacetate in benzene gave17α-ethyl-17β-hydroxy-desA-androst-9-en-5-one, which after sublimation(140° and 0.1 mm. Hg vacuum), was obtained as a glass. [α]_(D) ²⁵ -36.6°(c = 1, CHCl₃).

EXAMPLE 4

A suspension of 262 mg. of 5 per cent rhodium on alumina catalyst in amixture of 26 ml. of 95 per cent ethanol and 5.25 ml. of 2N sodiumhydroxide solution was pre-reduced, (i.e. hydrogenated at roomtemperature and atmospheric pressure). To this was added a solution of262 mg. of 17α-ethyl-17β-hydroxy-desA-androst-9-en-5-one in 15 ml. of 95per cent ethanol, and the mixture then hydrogenated at atmosphericpressure and room temperature. After one mole-equivalent of hydrogen wasabsorbed, the reaction was stopped, the catalyst was separated byfiltration, and the filtrate evaporated in vacuo. Glacial acetic acid (1ml.) was added to the residue, which was then dissolved in 1 liter ofether. The cloudy solution which resulted was washed with 2N Na₂ CO₃solution, then with water, dried and evaporated to dryness in vacuo.

The reaction was repeated 3 more times, and the combined productschromotographed on a Florisil (adsorbent) column. The eluates with 1 percent ethyl acetate in benzene gave first crystalline fractions, whichwere followed by non-crystalline fractions. The non-crystallinefractions were dissolved in 100 ml. of methylene chloride, and after theaddition of 2.5 ml. of 2 per cent CrO₃ in 90 per cent acetic acid,stirred overnight. The excess of chromic acid was removed by washing themethylene chloride solution with 10 ml. of 10 per cent sodium hydrogensulfite solution, following by washing with 2N Na₂ CO₃ solution and thenwith water. It was then dried and evaporated in vacuo. The residue wasdissolved in 50 ml. of anhydrous ethanol containing 172 mg. of sodiumethoxide, and left overnight. The next day, after addition of 0.5 ml. ofglacial acetic acid, the solution was evaporated in vacuo, and theresidue was taken up in 1 liter of ether. The ether solution was washedwith 2N Na₂ CO₃ solution, then with water, dried and evaporated. Theresidue was chromatographed on Florisil (adsorbent) column and gavecrystalline 17α-ethyl-17β-hydroxy-desA-9β ,10β-androstan-5-one identical(by thin layer chromatography) with the crystalline material obtained inthe first chromatographic separation. After two recrystallizations fromether, it melted at 142°-144°; [α]_(D) ²⁵ -11.65° [methanol, c = 1.245per cent].

EXAMPLE 5

To a solution of 132 mg. of 17α-ethyl-17β-hydroxy-desA-9β,10β-androstan-5-one in 12.5 ml. of absolute ethanol containing 34 mg.of sodium ethoxide, 0.15 ml. of freshly distilled methylvinyl ketone wasadded. The reaction mixture was then refluxed for two hours in anitrogen atmosphere. After cooling the reaction mixture, 0.1 ml. ofglacial acetic acid was added thereto and the resulting mixture was thenpoured into 1 liter of ether. The resultant ether solution was washedwith water, dried over anhydrous sodium sulfate and evaporated in vacuo.The residue was chromatographed on fluorescent silica-gel plates, withthe solvent system, 60 per cent ethyl acetate-40 per cent heptane. Thefluorescent part of the layers was extracted with ethyl acetate. Theresidue obtained after evaporation of ethyl acetae was firstcrystallized from ether-petroleum ether, then a second time from pureether, yielding 17β-ethyl-9β ,10α-testosterone, m.p. 131°-135°.

EXAMPLE 6

A solution of 6.4 g. of 11α-hydroxy-progesterone in 100 ml. ofethylacetate and 50 ml. of methylene chloride was treated with ozone at-70° until the solution became blue in color. Oxygen was then passedthrough and the solution evaporated at room temperature in vacuo. Theso-obtained syrupy residue was dissolved in 100 ml. of glacial aceticacid, and after the addition of 5 ml. of 30 per cent hydrogen peroxide,left for 24 hours at 2° (in an ice box). The solution was thenevaporated in vacuo, and the residue triturated with ether yieldingcrystals. Recrystallization from acetone yielded11α-hydroxy-3,5-seco-A-nor-pregnane-5,20-dione-3-oic acid 3,11-lactone,m.p. 253°-256°. [α]_(D) ²⁵ +193.3° (c = 1, in chloroform).

EXAMPLE 7

A methanolic solution of 7.5 g. of11α-hydroxy-3,5-seco-A-nor-pregnane-5,20-dione-3-oic acid 3,11-lactonewas treated with one equivalent of 10N sodium hydroxide solution andthen evaporated to dryness. Sodium phenylacetate (26 g.) was added tothe so-obtained sodium salt and the mixture pyrolyzed at 295° for twohours in vacuo. The crude sublimate was chromatographed on a silica-gelcolumn and eluted with 10 per cent ethylacetate in benzene. Theamorphous solid 11α-hydroxy-10α-desA-pregnane-5,20-dione was firsteluted from the column. IR-spectrum in chloroform: 3620 and 3600cm.sup.⁻¹ (--OH); 1706 cm.sup.⁻¹ (carbonyl group). NMR-spectrum indeuterochloroform: a doublet for 10α-CH₃ at 73.5 and 80.5 c.p.s.,downfield from TMS at 60 Mc/sec. Further elution of the column with 10per cent ethylacetate in benzene yielded crystalline11α-hydroxy-10β-desA-pregnane-5,20 -dione which was recrystallized frommethylene chloride-petroleum ether, m.p. 150°-152°; [α]_(D) ²⁵ +84.0° (c= 0.5 in absolute ethanol).

EXAMPLE 8

To a solution of 100 mg. of methanesulfonylchloride in 0.7 ml. ofpyridine, there was added 100 mg. of11α-hydroxy-10β-desA-pregnane-5,20-dione. The mixture was then allowedto stand overnight at 2° (in a refrigerator), then was diluted withwater (100 ml.) and extracted with chloroform (3 × 150 ml.) andmethylene chloride (100 ml.). The combined organic extracts were washedwith water, 1N hydrochloric acid and again with water, then dried overanhydrous sodium sulfate and evaporated in vacuo. The crystallineresidue was recrystallized from ether, giving11α-hydroxy-10β-desA-pregnane-5,20-dione methanesulfonate, m.p.139°-140°; [α]_(D) ²⁵ +46° (c = 0.5 in absolute ethanol).

EXAMPLE 9

A solution of 200 mg. of 11α-hydroxy-10β-desA-pregnane-5,20-dionemethanesulfonate in 50 ml. of dimethylformamide was refluxed for eighthours and then evaporated to dryness. The residue was chromatographed ona Florisil (adsorbent) column. Elution with 2 per centethylacetate/benzene and evaporation of the eluant yieldeddesA-pregn-9-ene-5,20-dione in the form of colorless needles, m.p.111°-113°. It was shown by mixed melting point to be identical with asample of the same compound prepared as described in Example 12.

EXAMPLE 10

To a solution of 20 g. of 11α-hydroxy-progesterone in 150 ml. ofpyridine maintained at 0°, there was added 6 ml. ofmethanesulfonylchloride, and the reaction mixture allowed to standovernight at 0°. It was then diluted with a large excess of water andextracted with chloroform. The organic extracts were washed with 2Nhydrochloric acid and water, then dried over anhydrous sodium sulfateand evaporated in vacuo. The solid residue was recrystallized frommethanol to give 11α-mesyloxy-progesterone, m.p. 159.5°-160°; [α]_(D) ²⁵+145.6 (c = 1, chloroform).

EXAMPLE 11

A solution of 12 g. of 11α-mesyloxy-progesterone in 300 ml. of methylenechloride/ethyl acetate (2:1) was treated with ozone at -70° until thesolution became blue in color. The excess of ozone was removed bybubbling oxygen through the reaction mixture for five minutes. Methylenechloride was then removed under reduced pressure, and the solutiondiluted with ethyl acetate to 200 ml. After addition of 12 ml. of 30 percent aqueous hydrogen peroxide, the reaction mixture was then allowed tostand overnight at 2° (i.e., in the refrigerator), then evaporated to avolume of 75 ml. and diluted with 125 ml. of benzene. The aqueoussolution, obtained by extraction with 8 portions of 75 ml. 2N sodiumcarbonate followed by combining the aqueous extracts was acidified withcold concentrated hydrochloric acid to pH 2 and extracted with methylenechloride. This extract was dried over anhydrous sodium sulfate andevaporated in vacuo in dryness. The residue crystallized when trituratedwith ether-acetone mixture, yielding crude11α-mesoxy-5,20-dioxo-3,5-seco-A-nor-pregnan-3-oic acid. Afterrecrystallization from acetone-petroleum ether, m.p. 152°-153°; [α]_(D)²⁵ +47.9° (c = 1, chloroform).

EXAMPLE 12

A solution of 6 g. of 11α-mesoxy-5,20-dioxo-3,5-seco-A-nor-pregnan-3-oic acid in 150 ml. of methanol wasmixed with a solution of 1.5 g. of sodium carbonate in 55 ml. of water.The mixture was then transferred into a 1 liter sublimation flask, andevaporated to dryness. To the thus formed sodium salt, 20 g. of sodiumphenyl acetate is added, and after closing the top part of theapparatus, this mixture was pyrolyzed at 290° and 0.02 mm. for fourhours. The product, which collects on the cold finger, was dissolved inether and filtered. The filtrate was then evaporated to dryness.Purification of the residue by chromatography on a 40 g. silica-gelcolumn (benzene eluant) gave crystalline desA-pregn-9-ene-5,20-dione;m.p. 111°-113° (after recrystallization from ether). [α]_(D) ²⁵ +56.8°(c = 0.25 per cent in methanol).

EXAMPLE 13

To a solution of 1.2 g. of desA-pregn-9-ene-5,20-dione in 20 ml. ofmethanol maintained at 0°, there was slowly added a cooled solution of1.2 g. of sodium borohydride in 22 ml. methanol, and the resultantmixture was left for 72 hours at 0°. It was then diluted with 100 ml. ofwater and extracted with four 100 ml. portions of chloroform. Theextract was dried over anhydrous sodium sulfate and evaporated in vacuo,yielding a colorless oily product. This product was dissolved in 250 ml.of chloroform and 6 g. of manganese dioxide was added to the solutionwhich was then stirred for 72 hours at room temperature, filtered andthe filtrate evaporated to dryness in vacuo. The residue waschromatographed on a silica-gel column and the eluates with 5 per centethyl acetate in benzene, after concentration gave crystalline20β-hydroxy-desA-pregn-9-en-5-one which upon recrystallization frommethylene chloride-petroleum ether formed colorless needles, m.p.122°-123°; [α ]_(D) ²⁵ -33° (c = 0.5, absolute ethanol).

EXAMPLE 14

A suspension of 262 mg. of 5 per cent rhodium on alumina catalyst in amixture of 26 ml. of 95 per cent ethanol and 5.25 ml. of 2N aqueoussodium hydroxide was hydrogenated at room temperature and atmosphericpressure. To this was added a solution of 262 mg. of20β-hydroxy-desA-pregn-9-en-5-one in 15 ml. of 95 per cent ethanol, andthe reaction mixture then hydrogenated at room temperature andatmospheric pressure. After one mole equivalent of hydrogen wasabsorbed, the reaction was stopped, and the catalyst was separated byfiltration. After standing overnight the filtrate was concentrated invacuo. To the residue was added 1 ml. of glacial acetic acid, and it wasthen dissolved in 1 liter of ether. The cloudy solution was washed with2N aqueous sodium carbonate solution, then with water, then dried overanhydrous sodium sulfate and evaporated to dryness in vacuo. It yieldeda colorless oil, which was chromatographed on a silica-gel column using1 per cent ethyl acetate in benzene as the elutant. First eluted was20β-hydroxy-10α-desA-pregnan-5-one, m.p. 107°-108° afterrecrystallization from methylene chloride/petroleum ether. R.D. (inmethanol); [α]₅₀₀ - 25.3°, -[α]₄₀₀ -89° ; [α]₃₅₀ -274°; [α]₃₀₅ -1335°;[α]₃₀₀ -1165°.

Further elution yielded 20β-hydroxy-9β ,10β-desA-pregnan-5-one as acolorless oil. R. D. (in methanol); [α]₅₀₀ -14.8°; [α]₄₀₀ -4.4°; [α]₃₅₀+22.2°; [α]₃₁₀ +2148°.

EXAMPLE 15

A suspension of 262 mg. of 5 per cent rhodium on alumina catalyst in amixture of 2 ml. of 3N aqueous hydrochloric acid and 18 ml. 95 per centethanol was hydrogenated at room temperature and atmospheric pressure. Asolution of 262 mg. of 20β-hydroxy-desA-pregn-9-en-5-one in 5 ml. ofabsolute ethanol was introduced into the hydrogenation flask, and thereaction mixture was then hydrogenated at room temperature andatmospheric pressure. After one mole-equivalent of hydrogen wasabsorbed, the reaction was stopped, the catalyst was separated byfiltration, and the filtrate neutralized with 2N aqueous sodiumhydroxide solution. An excess of 5 ml. of 2N aqueous sodium hydroxidewas added and the solution allowed to stand overnight. Ethanol was thenremoved by evaporation at reduced pressure, and after addition of 1 ml.of glacial acetic acid, it was extracted with 1 liter of ether. Theextract was washed with 2N aqueous sodium carbonate solution, then withwater, dried and concentrated in vacuo. It gave a colorless oil, whichwas chromatographed on a silica-gel column using 2 per cent ethylacetate in benzene as the elutant. The first fractions of the eluateyielded, upon concentration, 20β-hydroxy-10α-desA-pregnan-5-one. Fromthe immediately subsequent fraction, 20β-hydroxy-9β,10β-desA-pregnan-5-one was obtained. Both products were identical with thesame compounds obtained in Example 14.

EXAMPLE 16

20β-Hydroxy-9β ,10α-pregn-4-en-3-one is prepared by condensation of20β-hydroxy-9β ,10β-desA-pregnan-5-one with methyl vinyl ketoneaccording to the procedure of Example 5. The product melts at176.5°-178.5°; [α]_(D) ²⁵ -143° (chloroform).

EXAMPLE 17

A medium is prepared of 20 g. of Edamine enzymatic digest oflactalbumin, 3 g. of corn steep liquor and 50 g. of technical dextrosediluted to 1 liter with tap water and adjusted to a pH of 4.3 - 4.5.Twelve liters of this sterilized medium is inoculated with Rhizopusnigricans minus strain (A.T.C.C. 6227b) and incubated for 24 hours at28° using a rate of aeration and stirring such that the oxygen uptake is6.3 14 7 millimoles per hour per liter of Na₂ SO₃ according to themethod of Cooper et al, Ind. Eng. Chem., 36, 504 (1944). To this mediumcontaining a 24 hour growth of Rhizopus nigricans minus strain, 6 g. of17α-acetoxy-progesterone in 150 ml. of acetone is added. The resultantsuspension of the steroid in the culture is incubated under the sameconditions of temperature and aeration for an additional 24 hour periodafter which the beer and mycelium are extracted. The mycelium is thenfiltered, washed twice, each time with a volume of acetone approximatelyequal in volume to the mycelium, extracted twice, each time with avolume of methylene chloride approximately equal to the volume of themycelium. The acetone and methylene chloride extracts including solventare then added to the beer filtrate. The mixed extracts and beerfiltrate are then extracted successively with 2 portions of methylenechloride, each portion being one-half the volume of the mixed extractsand beer filtrate, and then with 2 portions of methylene chloride, eachportion being 1/4 the volume of the mixed extracts and beer filtrate.The combined methylene chloride extracts are then washed with 2 portionsof a 2 per cent aqueous solution of sodium bicarbonate, each portionbeing 1/10 the volume of the combined methylene chloride extracts. Themethylene chloride extracts are then dried with about 3 - 5 g. ofanhydrous sodium sulfate per liter of solvent, and then filtered. Thesolvent is then removed from the filtrate by distillation, and theresidue is dissolved in a minimum of methylene chloride, filtered andthe solvent evaporated from the filtrate. The resulting crystals arethen dried and washed five times, each time with a 5 ml. portion ofether per gram of crystal. The crystals are then recrystallized fromether giving 17α-acetoxy-11α-hydroxy-progesterone.17α-acetoxy-11α-mesoxy-progesterone is prepared by treatment of17α-acetoxy-11α-hydroxy-progesterone with methanesulfonyl chloride,according to the procedure of Example 10.

EXAMPLE 18

17α-Acetoxy-5,20 -dioxo-11α-mesoxy-A-nor-3,5-seco-pregnan-3-oic acid isprepared by ozonolysis of 17α-acetoxy-11α-mesoxy-progesterone, accordingto the procedure of Example 11.

EXAMPLE 19

17α-Acetoxy-desA-pregn-9-ene-5,20 -dione is prepared from17α-acetoxy-5,20-dioxo-11α-mesoxy-A-nor-3,5-seco-pregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 12.

EXAMPLE 20

17α-Acetoxy-20β-hydroxy-desA-pregn-9-en-5-one is prepared from17α-acetoxy-desA-pregn-9-en-5,20-dione by reduction and reoxidationaccording to the procedure of Example 13.

EXAMPLE 21

17α-Acetoxy-20β-hydroxy-9β ,10β-desA-pregnan-5-one is prepared from17α-acetoxy-20β-hydroxy-desA-pregn-9-en-5-one by hydrogenation underacidic conditions in the presence of a rhodium catalyst, according tothe procedure of Example 15.

EXAMPLE 22

17α-Acetoxy-20β-hydroxy-9β ,10α-pregn-4-en-3-one is prepared bycondensing methyl vinyl ketone with 17α-acetoxy-20β-hydroxy-9β,10β-desA-pregnan-5-one according to the procedure of Example 5 exceptinstead of conducting the condensation in absolute ethanol andcatalyzing it with sodium ethoxide, the condensation is conducted inacetic acid and is catalyzed with p-toluene solfonic acid.

EXAMPLE 23

20β-Hydroxy-4-methyl-9β ,10α-pregn-4-en-3-one is prepared by condensing20β-hydroxy-9β,10β-desA-pregnan-5-one and ethyl vinyl ketone accordingto the procedure of Example 5.

EXAMPLE 24

17β-Hydroxy-5-oxo-3,5-seco-A-nor-androstan-3-oic acid is prepared byozonolysis of testosterone according to the procedure of Example 1.

EXAMPLE 25

17β-Hydroxy-10α-desA-androstan-5-one and17β-hydroxy-10β-desA-androstan-5-one are prepared from17β-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid by conversion ofthe latter to its sodium salt followed by pyrolysis, according to theprocedure of Example 2.

EXAMPLE 26

17β-Hydroxy-desA-androst-9-en-5-one is prepared from17β-hydroxy-10α-desA-androstan-5-one by bromination followed bydehydrobromination, according to the procedure of Example 3.

EXAMPLE 26a

DesA-androst-9-ene-5,17-dione is prepared from17β-hydroxy-desA-androst-9-en-5-one by oxidation of the latter with a 2per cent chromic acid solution in 90 per cent acetic acid. Theso-obtained desA-androst-9-ene-5,17-dione is recrystallized fromcyclohexane and melts at 123°-123.5°; ]α]₅₈₉ ²⁵ = + 83° (c = 0.1021,dioxane).

EXAMPLE 27

A solution of 236 mg. of 17β-hydroxy-desA-androst-9-en-5-one in 40 ml.95 per cent ethanol and 5.25 ml. 2N aqueous sodium hydroxide solutionwas hydrogenated with one mole equivalent of hydrogen over 236 mg. ofprereduced 5 per cent rhodium on alumina catalyst. After separation ofcatalyst, the solution was concentrated in vacuo to dryness, and theresidue taken up in one liter of ether. The ether solution was washedwith water, dried over anhydrous sodium sulfate and evaporated todryness in vacuo. From the residue 17β-hydroxy-9β,10β-desA-androstan-5-one was obtained by crystallization. M.p.144.5°-145°; [α]_(D) ²⁵ -22° (c = 0.103; dioxane). The 17β-acetate(i.e., 17β-acetoxy-962 ,10β-desA-androstan-5-one) is obtained byacetylation of testosterone followed by ozonolysis, pyrolysis,bromination and dehydrobromination, and reduction according to themethod of Examples 24, 25, 26 and 27 respectively, and melts at118°-119°; [α]_(D) ²⁵ -28° (c = 0.103; dioxane).

EXAMPLE 28

A solution of 238 mg. of 17β-hydroxy-9β,10β-desA-androstan-5-one, 1 ml.of ethylene glycol and catalytic amount of p-toluene sulfonic acid in100 ml. of anhydrous benzene was slowly distilled until no more waterwas coming over. The solution was then concentrated in vacuo to a smallvolume, and 17β-hydroxy-9β ,10β-desA-androstan-5-one 5-ethylene ketalwas obtained from the residue by crystallization. M. p. 115°-116°;[α]_(D) ²⁵ -9° (c = 0.0987; dioxane).

EXAMPLE 29

To a solution of 282 mg. of 17β-hydroxy-9β,10β-desA-androstan-5-one5-ethylene ketal in 50 ml. of methylene chloride was added 1 equivalentof 2 per cent chromic acid in pyridine, and the reaction mixture thenstirred overnight. The reaction mixture was then washed with 10 per centaqueous sodium hydrogen sulfite, 2N aqueous sodium carbonate, water,then dried over anhydrous sodium sulfate and concentrated in vacuo todryness. Crystallization of the residue gave9β,10β-desA-androstane-5,17-dione 5-monoethylene ketal. Splitting of theketal in acetone solution in the presence of a catalytic amount ofp-toluene sulfonic acid gives 9β,10β-desA-androstane-5,17-dione whichmelts, after recrystallization from cyclohexane, at 77.5°-78°; [α]_(D)25 +55° (c = 0.107; dioxane).

EXAMPLE 30

To a preformed solution of one mole equivalent of prop-1'-inyl lithiumin 100 ml. of anhydrous liquid ammonia was added tetrahydrofuransolution of 200 mg. of 9β,10β-desA-androstane-5,17-dione 5-mono-ethyleneketal, and the reaction mixture stirred for two hours. After addition ofone gram of ammonium chloride, cooling was discontinued, and thereaction mixture allowed to evaporate. The residue was extracted withmethylene chloride, the extract was washed with water, dried overanhydrous sodium sulfate and evaporated. The residue was dissolved in 20ml. of acetone and the catalytic amount of p-toluenesulfonic acid added,and the solution was refluxed for two hoours, then poured in water andextracted in methylene chloride. The methylene chloride extract waswashed with water, then dried over anhydrous sodium sulfate andevaporated to dryness in vacuo. Crystallization of the residue gave17α-(prop-1'-inyl)-17β-hydroxy-9β,10β-desA-androstan-5-one.

EXAMPLE 31

17α-(prop-1'-inyl)-17β-hydroxy-9β,10α-androstan-4-en-3-one is preparedby condensing methyl vinyl ketone with17α-(prop-1'-inyl)-17β-hydroxy-9β,10β-desA-androstan-5-one according tothe procedure of Example 5. The product melts at 164°-165°.

EXAMPLE 32

To a stirred solution of one mole equivalent of 2-methylprop-2-enylmagnesium bromide in 100 ml. of ether at room temperature was addeddropwise a solution of 280 mg. of 9β,10β-desA-androstane-5,17-dione5-mono-ethylene ketal in 100 ml. of tetrahydrofuran. The reactionmixture was refluxed for one hour. After cooling in an ice-salt bath, asaturated solution of sodium sulfate was slowly added to decompose theGrignard complex. This was followed by addition of anhydrous sodiumsulfate. The solution was separated by filtration and concentrated invacuo to dryness. The solution of the residue and of a catalytic amountof p-toluene sulfonic acid in 20 ml. of acetone was refluxed for twohours, then poured in water and extracted in methylene chloride.Methylene chloride extract was washed with water, dried over anhydroussodium sulfate and evaporated to dryness. From the residue17α-(2'-methyl-prop-2'-enyl)-17β-hydroxy-9β,10β-desA-androstan-5-one wasobtained.

EXAMPLE 33

17α-(2'-methyl-prop-2'-enyl)-17β-hydroxy-9β,10α-androst-4-en-3-one isprepared from17α-(2'-methyl-prop-2'-enyl)-17β-hydroxy-9β,10β-desA-androstan-5-one bycondensation of the latter with methyl vinyl ketone according to theprocedure of Example 5. The product melts at 106°-108°.

EXAMPLE 34

16α-Acetoxy-20-ethylenedioxy-pregn-4-en-3-one is prepared by acetylationof 16α-hydroxy 20-ethylenedioxy-pregn-4-ene-3,20-dione with oneequivalent of acetic anhydride in pyridine solution at room temperaturefor 2 hours, followed by concentration to dryness in vacuo.16α-Acetoxy-20-ethylenedioxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid isprepared by ozonolysis of 16α-acetoxy-20-ethylenedioxy-pregn-4-en-3-oneaccording to the procedure of Example 1.

EXAMPLE 35

16α-Acetoxy-20-ethylenedioxy-10α-desA-pregnan-5-one and 16α-acetoxy-20-ethylenedioxy-10β-desA-pregnan-5-one are prepared from16α-acetoxy-20-ethylenedioxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis(according to the procedure of Example 2) and reacetylation with aceticanhydride and pyridine.

EXAMPLE 36

16α-Acetoxy-20-ethylenedioxy-desA-pregn-9-en-5-one is prepared from16α-acetoxy-20-ethylenedioxy-10α-desA-pregnan-5-one by brominationfollowed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 37

16α-Acetoxy-20-ethylenedioxy-9β,10β-desA-pregnan-5-one is prepared from16α-acetoxy-20-ethylenedioxy-desA-pregn-9-en-5-one by hydrogenationunder basic conditions in the presence of a rhodium catalyst, accordingto the procedure of Example 14.

EXAMPLE 38

16α-Hydroxy-20-ethylenedioxy-9β,10α-pregn-4-en-3-one is prepared bycondensing 16α-acetoxy-20-ethylenedioxy-desA-9β,10β-pregnan-5-one withmethyl vinyl ketone according to the procedure of Example 5.

EXAMPLE 39

3β-Hydroxy-16α-methyl-pregn-5-en-20-one ethylene ketal is prepared byketalization of 3β-hydroxy-16α-methyl-pregn-5-en-20-one in benzenesolution with ethylene glycol using p-toluenesulfonic acid as catalyst.Pyridine-chromic acid oxidation of the so-obtained3β-hydroxy-16α-methyl-pregn-5-en-20-one ethylene ketal yields16α-methyl-20-ethylenedioxy-pregn-4-en-3-one.16α-methyl-20-ethylenedioxy-5-oxo-3,5-seco-A-norpregnane-3-oic acid isprepared by ozonolysis of 16α-methyl-20-ethylene-dioxy-pregn-4-en-3-oneaccording to the procedure of Example 1.

EXAMPLE 40

16α-Methyl-20-ethylenedioxy-10α-desA-pregnan-5-one and16α-methyl-20-ethylenedioxy-10β-desA-pregnan-5-one are prepared from16α-methyl-20-ethylenedioxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 2.

EXAMPLE 41

16α-Methyl-20-ethylenedioxy-desA-pregn-9-en-5-one is prepared from16α-methyl-20-ethylenedioxy-10α-desA-pregnan-5-one by brominationfollowed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 42

16α-Methyl-20-ethylenedioxy-9β,10β-desA-pregnan-5-one is prepared from16α-methyl-20-ethylenedioxy-desA-pregn-9-en-5-one by hydrogenation underbasic conditions in the presence of a rhodium catalyst, according to theprocedure of Example 14.

EXAMPLE 43

16α-Methyl-20-ethylenedioxy-9β,10α-pregn-4-en-3-one is prepared bycondensing 16α-methyl-20-ethylenedioxy-9β,10β-desA-pregnan-5-one withmethyl vinyl ketone, according to the procedure of Example 5.

EXAMPLE 44

21-Acetoxy-11α-hydroxy-20-ethylenedioxy-pregn-4-en-3-one is prepared bymicrobiological treatment of21-acetoxy-20-ethylenedioxy-pregn-4-en-3-one, according to the procedureof Example 17. 21-Acetoxy-11α-mesoxy-20-ethylenedioxy-pregn-4-en-3-oneis prepared by treatment of21-acetoxy-11α-hydroxy-20-ethylenedioxy-pregn-4-ene-3-one withmethanesulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 45

21-Acetoxy-11α-mesoxy-20-ethylenedioxy-5-oxo-3,5-seco-A-norpregnan-3-oicacid is prepared by ozonolysis of21-acetoxy-11α-mesoxy-20-ethylenedioxy-pregn-4-en-3-one, according tothe procedure of Example 11.

EXAMPLE 46

21-Acetoxy-20-ethylenedioxy-desA-pregn-9-en-5-one is prepared from21-acetoxy-20-ethylenedioxy-11α-mesoxy-3,5-seco-A-norpregnan-3-oic acidby conversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 12, except that the crude productis reacetylated by treatment with acetic anhydride/pyridine prior to itsbeing worked-up.

EXAMPLE 47

21-Acetoxy-20-ethylenedioxy-9β,10β-desA-pregnan-5-one is prepared from21-acetoxy-20-ethylenedioxy-desA-pregn-9-en-5-one by hydrogenation underacidic conditions in the presence of a rhodium catalyst, according tothe procedure of Example 15.

EXAMPLE 48

21-Hydroxy-20-ethylenedioxy-9β,10α-pregn-4-en-3-one is prepared from21-acetoxy-20-ethylenedioxy-9β,10β-desA-pregnan-5-one by condensing thelatter with methyl vinyl ketone, according to the procedure of Example22.

EXAMPLE 49

11α-Mesoxy-16α,17α-isopropylidenedioxy-progesterone is prepared bytreatment of 11α-hydroxy-16α,17α-isopropylidenedioxy-progesterone withmethane sulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 50

5,20-dioxo-11α-mesoxy-16α,17α-isopropylidenedioxy-3,5-seco-A-norpregnan-3-oicacid is prepared by ozonolysis of11α-mesoxy-16α,17α-isopropylidenedioxy-progesterone, according to theprocedure of Example 11.

EXAMPLE 51

16α,17α-isopropylidenedioxy-desA-pregn-9-en-5,20-dione is prepared from5,20-dioxo-11α-mesoxy-16α,17α-isopropylidenedioxy-3,5-seco-A-norpregnan-3-oicacid by conversion of the latter to its sodium salt, followed bypyrolysis according to the procedure of Example 12.

EXAMPLE 52

20β-Hydroxy-16α,17α-isopropylidenedioxy-desA-pregn-9-en-5-one isprepared from 16α,17α-isopropylidenedioxy-desA-pregn-9-ene-5,20-dione byreduction and reoxidation, according to the procedure of Example 13.

EXAMPLE 53

20β-Hydroxy-16α,17α-isopropylidenedioxy-9β,10β-desA-pregnan-5-one isprepared from20β-hydroxy-16α,17α-isopropylidenedioxy-desA-pregn-9-en-5-one byhydrogenation according to the procedure of Example 14.

EXAMPLE 54

20β-Hydroxy-16α,17α-isopropylidenedioxy-9β,10α-pregn-4-en-3-one isprepared by condensing methyl vinyl ketone with20β-hydroxy-16α,17α-isopropylidenedioxy-desA-9β,10.beta.-pregnan-5-oneaccording to the procedure of Example 5.

EXAMPLE 55

7α,17α-dimethyl-17β-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid isprepared from 7α,17α-di-methyl-testosterone by ozonolysis of the latter,according to the procedure of Example 1.

EXAMPLE 56

7α,17α-dimethyl-17β-hydroxy-10α-desA-androstan-5-one and 7α,17α-dimethyl17β-hydroxy-10β-desA-androstan-5-one are prepared from7α,17α-dimethyl-17β-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 2.

EXAMPLE 57

7α,17α-dimethyl-17β -hydroxy-desA-androst-9-en-5-one is prepared from7α,17α-dimethyl-17β-hydroxy-10α-desA-androstan-5-one by brominationfollowed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 58

7α,17α-dimethyl-17β-hydroxy-desA-9β,10β-androstan-5-one is prepared from7α,17α-dimethyl-17β-hydroxy-desA-androst-9-en-5-one by hydrogenation inthe presence of a rhodium catalyst, according to the procedure ofExample 4.

EXAMPLE 59

7α,17α-dimethyl-9β,10α-testosterone is prepared from7α,17α-dimethyl-17β-hydroxy-desA-9β,10β-androstan-5-one by condensingthe latter with methyl vinyl ketone, according to the procedure ofExample 5.

EXAMPLE 60

11α-Mesoxy-17α-methyl-progesterone is prepared from11α-hydroxy-17α-methyl-progesterone by treatment of the latter withmethane sulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 61

11α-mesoxy-17α-methyl-5,20-dioxo-3,5-seco-A-norpregnan-3-oic acid isprepared from 11α-mesoxy-17α-methyl-progesterone by ozonolysis of thelatter, according to the procedure of Example 11.

EXAMPLE 62

17α-methyl-desA-pregn-9-ene-5,20-dione is prepared from11α-mesoxy-17α-methyl-5,20-dioxo-3,5-seco-A-norpregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 12.

EXAMPLE 63

20β-Hydroxy-17α-methyl-desA-pregn-9-en-5-one is prepared from17α-methyl-desA-pregn-9-en-5,20-dione according to the procedure ofExample 13.

EXAMPLE 64

20β-Hydroxy-17α-methyl-9β,10β-desA-pregnan-5-one is prepared from17α-methyl-20β-hydroxy-desA-pregnan-9-ene-5-one according to theprocedure of Example 15.

EXAMPLE 65

20β-Hydroxy-17α-methyl-9β,10α-pregn-4-en-3-one is prepared by condensing17α-methyl-20β-hydroxy-9β,10β-desA-pregnan-5-one with methyl vinylketone, according to the procedure of Example 4.

EXAMPLE 66

A solution of 12.8 g. of 17α-methyltestosterone in 200 ml. of methylenechloride and 100 ml. of ethyl acetate was ozonized for 1 hour and 5minutes at -70° (acetone-dry ice bath) until a blue color developed.After oxygen was bubbled through, the solution was then concentrated atroom temperature in vacuo. The residue was dissolved in 400 ml. ofacetic acid, and after addition of 30 ml. of 30% hydrogen peroxide, thesolution was left overnight at 0°. It was then evaporated to dryness invacuo, the residue taken up in ether, and the ether solution extractedwith 2N aqueous sodium carbonate (12 × 50 ml.). The combined carbonateextracts were cooled in ice, and acidified with concentratedhydrochloric acid. The aqueous suspension of precipitated organic acidwas extracted with methylene chloride, this extract was washed withwater, dried over anhydrous sodium sulfate and evaporated giving as acolorless crystalline material17β-hydroxy-17α-methyl-5-oxo-3,5-seco-A-nor-androstan-3-oic acid. Afterrecrystallization from acetone-hexane, it melted at 195°-197°, [α]_(D)²⁵ = 9.8°(c = 1.0 in chloroform).

EXAMPLE 67

A solution of 10 g. of17β-hydroxy-17α-methyl-5-oxo-3,5-seco-A-nor-androstan-3-oic acid in 250ml. of methanol was made alkaline to phenolphthalein with sodiumethoxide, and evaporated to dryness. The residual powdery sodium saltwas mixed well with 32 g. of sodium phenylacetate and 40 g. of neutralalumina (Woelm, Grade I), and the mixture heated at 290° in vacuo for 4hours. After cooling to room temperature, a large excess of water wasadded, and the resultant suspension extracted with 2 liters of ether.The ether extract was washed with water, aqueous 2N sodium carbonatesolution, and again with water, dried and evaporated. This gave a sirupyresidue, which by thin layer chromatograms and infrared spectraconsisted of 17β-hydroxy-17α-methyl-10α-desA-androstan-5-one as themajor and 17β-hydroxy-17α-methyl-10β-desA-androstan-5-one as the minorproduct.

Three additional pyrolyses were performed as described above, and thecombined products so-obtained was chromatographed on a 850 g. silica gelcolumn, using 5% ethylacetate in benzene as the eluent. Thischromatography yielded 17β-hydroxy-17α-methyl-10α-desA-androstan-5-one,which after recrystallization from petroleum ether melted at 96°-97°,[α]_(D) ²⁵ = 28.2° (c = 0.5 in chloroform).

Further eluates of the column gave product,17β-hydroxy-17α-methyl-10β-desA-androstan-5-one which, whenrecrystallized from ether, melted at 165°-167°, [α]_(D) ²⁵ = -19.8° (c =0.5 in chloroform).

To a solution of 2.2 g. of the mixture of17β-hydroxy-17α-methyl-10α-desA-androstan-5-one and17β-hydroxy-17α-methyl-10β-desA-androstan-5-one (obtained by the abovepyrolysis procedure) in 50 ml. of absolute ethanol were added 20.1 ml.of a solution prepared by dissolving 2.48 g. of sodium metal in 250 ml.of absolute ethanol. The reaction mixture was stirred overnight at roomtemperature. It was then acidified with 2 ml. of glacial acetic acid,and evaporated to dryness. The residue was extracted in ether (1 liter)and the ether extract washed with water, dried, and evaporated. Theresidue was crystallized from petroleum ether giving a quantitativeyield of 17β-hydroxy-17α-methyl-10α-desA-androstan-5-one.

EXAMPLE 68

To a solution of 11.2 g. of17β-hydroxy-17α-methyl-10α-desA-androstan-5-one in 1260 ml. of anhydrousether, stirred and cooled in an ice-salt bath, were added first severaldrops of 30% hydrogen bromide in acetic acid, then dropwise a solutionof 7.16 g. of bromine in 20 ml. of glacial acetic acid. The rate ofaddition of the bromine solution was synchronized with the rate ofdisappearance of excess bromine. After bromination was complete, 53 ml.of 10% sodium hydrogen sulfite solution and 53 ml. of aqueous 2N sodiumcarbonate solution were added to the reaction mixture while stirring.The ether layer was then separated, washed with water, dried, andevaporated to dryness in vacuo. The residue was dissolved in 250 ml. ofdimethylformamide, and heated with 7.5 g. of lithium carbonate at 100°for 45 minutes. After cooling, 2 liters of ether were added and theether solution washed with water, 1N hydrochloric acid, and then againwith water, dried and evaporated. The residue was dissolved in 200 ml.of glacial acetic acid, 12.6 g. of sodium acetate and 12.6 g of zincpowder were added and the mixture heated for ten minutes at 80°. Aftercooling to room temperature, the reaction mixture was filtered, andevaporated. The residue was dissolved in ethylacetate, and washed withsaturated sodium bicarbonate solution, then with water, dried andevaporated. The so-obtained residue was chromatographed on a silica gelcolumn using 10% ethylacetate in benzene as the eluent which gave first17β-hydroxy-17α-methyl-10α-desA-androstan-5-one, followed by17β-hydroxy-17α-methyl-desA-androst-9-en-5-one. After recrystallizationfrom ether, the latter compound melted at 103°-104°, [α]_(D) ²⁵ = -63.2°(c = 0.5 in chloroform).

EXAMPLE 69

A suspension of 1.25 g. of 5% rhodium on alumina catalyst in a mixtureof 130 ml. of 95% ethanol and 26 ml. of 2N sodium hydroxide wasprereduced. To this was then added a solution of 1.25 g. of17β-hydroxy-17α-methyl-desA-androst-9-en-5-one in 75 ml. of 95% ethanol,and then the mixture was hydrogenated at atmospheric pressure and roomtemperature. After one mole equivalent of hydrogen was absorbed, thereaction was stopped, the catalyst was removed by filtration, and thefiltrate evaporated in vacuo. To the residue 5 ml. of glacial aceticacid was added, the so-formed mixture then dissolved in 2 liters ofether, and the resultant cloudy solution was washed with water, thendried and evaporated. The residue was dissolved in 50 ml. of methylenechloride and oxidized with 5 ml. of 2% chromic acid in 90% acetic aciduntil green color of reaction mixture. After then being washed withsodium hydrogen sulfite solution 2N sodium carbonate solution and water,the reaction mixture was dried over sodium sulfate and evaporated. Theresidue was chromatographed very slowly on a 50 g. silica gel column,with 5% ethylacetate in benzene, and followed with thin layerchromatography. First,17β-hydroxy-17α-methyl-9α,10α-desA-androstan-5-one was eluted. After aminor amount of mixed material,17β-hydroxy-17α-methyl-9β,10β-desA-androstan-5-one was eluted. Afterrecrystallization from ether-petroleum ether, it melted at 94°-96°.

EXAMPLE 70

17α-Methyl-9β,10α-testosterone is prepared from17α-methyl-17β-hydroxy-desA-9β,10β-androstan-5-one by condensation ofthe latter with methyl vinyl ketone, according to the procedure ofExample 5. The product melts at 128°-129°.

EXAMPLE 71

A solution of 6 g. of 11α,20β-diacetoxy-pregn-4-en-3-one in 100 ml.methylene chloride and 50 ml. of ethylacetate was ozonized at -70°.After methylene chloride was removed by distillation in vacuo, theresidual solution was diluted to 100 ml. with ethylacetate. To this 5ml. of 30 per cent hydrogen peroxide was added and left overnight atroom temperature. The reaction mixture was concentrated to dryness invacuo, the residue taken up in 1 liter of ether, and the resultingsolution extracted 10 times with 50 ml. portions of 2N aqueous sodiumcarbonate. The carbonate extract was then acidified with ice-coldconcentrated hydrochloric acid. The precipitated product was separatedby filtration, and crystallized to give11α,20β-diacetoxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid.

EXAMPLE 72

A methanolic solution of 5 g. of11α,20β-diacetoxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid was treatedwith one-half mole equivalent of sodium carbonate, and evaporated todryness in vacuo. Potassium acetate (5 g.) was added to the residuewhich was then pyrolyzed at 295° and 0.02 mm. The sublimate waschromatographed on a silica-gel column to give11α,20β-diacetoxy-10β-desA-pregnan-5-one.

EXAMPLE 73

Bromination and dehydrobromination starting with11α,20β-diacetoxy-10β-desA-pregnan-5-one according to the procedure ofExample 3, gave 11α,20β-diacetoxy-desA-pregn-9-en-5-one.

EXAMPLE 74

Hydrogenation of 11α,20β-diacetoxy-desA-pregn-9-en-5-one in ethanolichydrochloric acid over 5 per cent rhodium on alumina catalyst at roomtemperature and atmospheric pressure according to the procedure ofExample 15 gave 11α,20β-diacetoxy-9β,10β-desA-pregnan-5-one.

EXAMPLE 75

11α,20β-Diacetoxy-9β,10β-desA-pregnan-5-one was hydrolyzed in methanolsolution with one mole equivalent of potassium carbonate to give11α,20β-dihydroxy-9β,10β-desA-pregnan-5-one.

EXAMPLE 76

Condensation of 11α,20β-dihydroxy-9β,10β-desA-pregnan-5-one with methylvinyl ketone according to the procedure of Example 5 gave11α,20β-dihydroxy-9β,10α-pregn-4-en-3-one.

EXAMPLE 77

A solution of 3 g. of 17α-ethyl-17β-hydroxy-androsta-1,4-dien-3-one in75 ml. of methylene chloride and 25 ml. of ethyl acetate was ozonized at-70° till it became blue. After evaporation to dryness, the residue wasdissolved in 100 ml. of glacial acetic acid containing 5 ml. of 30 percent hydrogen peroxide, and set at room temperature for 2 days. Thereaction mixture was concentrated to dryness and the residue dissolvedin one liter of ether. The ether solution was then extracted 10 timeswith 25 ml. portions of aqueous 2N sodium carbonate solution, and thecarbonate extracts were acidified with ice-cold concentratedhydrochloric acid. The non-crystalline precipitate containing17α-ethyl-17β-hydroxy-10α-carboxy-desA-androstan-5-one was separated byfiltration and dried, then dissolved in 135 ml. of absolute ethanol, andafter addition of 9 ml. of aqueous 2N sodium hydroxide, boiled for 1 hr.The reaction mixture was concentrated in vacuo to a small volume, anddiluted with 1750 ml. of ether. The ether solution was washed withwater, dried over anhydrous sodium sulfate, and concentrated in vacuo todryness. The residue was crystallized from ether-petroleum ether, togive 17α-ethyl-17β-hydroxy-10α-desA-androstan-5-one, m.p. 89°-90°.

EXAMPLE 78

3-(17β-hydroxy-5-oxo-3,5-seco-A-nor-androstan-17α-yl-3-oicacid)-propionic acid lactone is prepared by ozonolysis of3-(3-oxo-17β-hydroxy-androst-4-en-17α-yl)-propionic acid lactone,according to the procedure of Example 1.

EXAMPLE 79

3-(17β-hydroxy-5-oxo-10α-desA-androstan-17α-yl)-propionic acid lactoneand 3-(17β-hydroxy-5-oxo-10β-desA-androstan-17α-yl)-propionic acidlactone are prepared from3-(17β-hydroxy-5-oxo-3,5-seco-A-nor-androstan-17α-yl-3-oicacid)-propionic acid lactone by conversion of the latter to its sodiumsalt followed by pyrolysis, according to the procedure of Example 2.

EXAMPLE 80

3-(17β-hydroxy-5-oxo-desA-androst-9-en-17α-yl)-propionic acid lactone isprepared from 3-(17β-hydroxy-5-oxo-10α-desA-androstan-17α-yl)-propionicacid lactone by bromination followed by dehydrobromination, according tothe procedure of Example 3.

EXAMPLE 81

3-(17β-hydroxy-5-oxo-9β,10β-desA-androstan-17α-yl)-propionic acidlactone is prepared from3-(17β-hydroxy-5-oxo-desA-androst-9-en-17α-yl)-propionic acid lactone byhydrogenation in the presence of a rhodium catalyst, according to theprocedure of Example 4.

EXAMPLE 82

3-(17β-hydroxy-3-oxo-9β,10α-androst-4-en-17α-yl)-propionic acid lactoneis prepared by condensing3-(17β-hydroxy-5-oxo-9β,10β-desA-androstan-17α-yl)-propionic acidlactone with methyl vinyl ketone, according to the procedure of Example5.

EXAMPLE 83

17α,20;20,21-bis-methylenedioxy-11α-mesyloxy-pregn-4-en-3-one isprepared by treatment of17α,20;20,21-bis-methylenedioxy-11α-hydroxy-pregn-4-en-3-one withmethanesulfonyl chloride according to the procedure of Example 10.

EXAMPLE 84

17α,20;20,21-bis-methylenedioxy-11α-mesyloxy-5-oxo-3,5-seco-A-norpregnan-3-oicacid is prepared by ozonolysis of17α,20;20,21-bis-methylenedioxy-11α-mesyloxy-pregn-4-en-3-one accordingto the procedure of Example 11.

EXAMPLE 85

17α,20;20,21-bis-methylenedioxy-desA-pregn-9-en-5-one is prepared from17α,20;20,21-bis-methylenedioxy-11α-mesyloxy-5-oxo-3,5-seco-A-norpregnan-3-oicacid by conversion of the latter to its sodium salt followed bypyrolysis, according to the procedure of Example 12.

EXAMPLE 86

17α,20;20,21-bis-methylenedioxy-9β,10β-desA-pregnan-5-one is preparedfrom 17α,20;20,21-bis-methylenedioxy-desA-pregn-9-en-5-one byhydrogenation in the presence of a rhodium catalyst according to theprocedure of Example 14.

EXAMPLE 87

17α,20;20,21-bis-methylenedioxy-9β,10α-pregn-4-en-3-one is prepared bycondensing methylvinyl ketone with17α,20;20,21-bis-methylenedioxy-9β,10β-desA-pregnan-5-one, according tothe procedure of Example 5.

EXAMPLE 88

20β-hydroxy-9β,10α-pregna-1,4-dien-3-one was prepared by condensation of20β-hydroxy-9β,10β-desA-pregnan-5-one with 1 equivalent of methylethinyl ketone in boiling benzene solution, catalyzed by sodium hydride.

EXAMPLE 89

One ml. of Jones Reagent (0.004 mole CrO₃) is added to 200 mg. of17β-hydroxy-9β,10β-desA-androstan-5-one in 20 ml. of acetone at -10°.The mixture is then left for 15 minutes at room temperature, and 5 ml.of ethanol then added. The resulting suspension is evaporated to drynessin vacuo, water is added to the residue and the undissolved moiety takenup in ether. The ether phase is then washed with a solution of sodiumbicarbonate and then with water, dried over sodium sulfate andevaporated to dryness. There is so obtained an oil which crystallizesupon the addition of a small portion of petroleum ether. The so-obtainedcrystals of 9β, 10β-desA-androstane-5,17-dione melt, afterrecrystallization from cyclohexane, at 77.5°-78°; [α]₅₈₉ ²⁵ +55°(c =0.107, dioxane); R.D. in dioxane (c = 0.107%): λ in mμ ([α]-value in °);550(+70); 400(+297); 350(+798); 320(+2968) max.; 300(+467); 299(0);290(-1890).

EXAMPLE 90

A solution of 250 mg. of 17β-hydroxy-9β ,10β-desA-androstan-5-onedissolved in 2.5 ml. of pyridine and 2.5 ml. of acetic anhydride, isleft at room temperature for 18 hours. The mixture is then evaporated todryness at 80°/11 mm., the residue taken up in ether, and the etherphase washed with 1N hydrochloric acid, sodium bicarbonate and water,and then dried over sodium sulfate. After filtration and evaporation ofthe ether, the residue is then treated with a small quantity ofpetroleum ether yielding crystals of17β-acetoxy-9β,10β-desA-androstan-5-one which, upon recrystallizationfrom methanol, melt at 118°-119°; [α]₅₈₉ ²⁵ ° = -28° (c = 0.103%,dioxane); R.D. in dioxane (c = 0.103%): λ in mμ ([α]-value in °); 400(-30); 356 (0); 350 (+10); 313 (+449) max.; 307 (+374) min.; 305 (+380)max.; 300 (+224); 293 (0); 280 (-652).

EXAMPLE 91

A solution of 250 mg. of 17β-acetoxy-9β,10β-desA-androstan-5-one in 60ml. of 95% methanol containing 144 mg. of potassium hydroxide isrefluxed for 60 minutes. The resulting mixture is evaporated to drynessin vacuo, water added to the residue and the suspension extracted withether. The ether phase is washed with water, dried over sodium sulfate,filtered off, the solvent removed and the crystalline residue thencrystallized from a small volume of cyclohexane, yielding crystals of17β-hydroxy-9β,10β-desA-androstan-5-one which upon being recrystallizedfrom ethylacetate melt at 144.5°-145°; [α]₅₈₉ ²⁵ = -22° (c = 0.103,dioxane), R.D. in dioxane (c = 0.103); λ in mμ ([α]-value in °); 400(-7); 390 (0); 350 (+52); 313 (+571) max.; 307 (+492) min.; 305 (+504)max; 300 (+324); 293 (0); 290 (-202).

EXAMPLE 92

A solution of 10 g. of 11β-formyloxy-androsta-1,4-diene-3,17-dione in100 ml. of acetic acid was ozonized at 0° until thin layerchromatography did not show any starting material. The reaction mixturewas then poured into 100 ml. of water and the mixture was then heated to100° for 30 minutes. The mixture was then concentrated in vacuo andtreated with 50 ml. of saturated sodium bicarbonate solution. Theundissolved material was extracted with 100 ml. of ether. The extractwas chromatographed on silica gel using methylene chloride. The eluateswere concentrated and gave, on addition of hexane,11β-formyloxy-10ε-desA-androstane-5,17-dione, m.p. 117°-117.5°(recrystallized from acetone-cyclohexane), [α]_(D) ²⁵ = 93° (dioxane).

EXAMPLE 93

By hydrolysis of 11β-formyloxy-10ε-desA-androstane-5,17-dione in 2%methanolic potassium hydroxide there is obtained11β-hydroxy-10ε-desA-androstan-5,17dione, which melts at 154°; [α]_(D)²⁵ +96° (dioxane).

EXAMPLE 94

250 mg. of 11β-hydroxy-10ε-desA-androstane-5,17-dione and 250 mg. ofp-toluene sulfonic acid monohydrate in 20 ml. of benzene were refluxedin a nitrogen atomosphere for 6 hours. The reaction mixture was thenwashed with an aqueous solution of sodium bicarbonate and then withwater, dried over sodium sulfate, filtered and evaporated to dryness.The residue was then chromatographed over silicagel (5 g.) indichloromethane. Triturating the residue obtained from the first 250 ml.eluted, yielded crystals of desA-androst-9-ene-5,17-dione, which uponrecrystallization from cyclohexane melted at 123°-123.5°.

EXAMPLE 95

The compound, 11β-formyloxy-5,17-dioxo-3,5-seco-A-norandrostan-3-oicacid is prepared from 11β-formyloxy-androst-4-ene-3,17-dione byozonolysis according to the procedure of Example 11. The so-obtainedproduct melts at 220°-221°; [α]_(D) ²⁵ +107° (dioxane).

EXAMPLE 96

3.7 g. of the sodium salt of11β-formyloxy-5,17-dioxo-3,5-seco-A-nor-androstan-3-oic acid and 12 g.of sodium phenylacetate are fused together in vacuo (0.1 Torr). When thebath temperature reaches 220° the molten mass begins to decompose. Thebath is then heated further (within 30 minutes) to a temperature of290°. Once this temperature has been reached the mixture is left foranother 10 minutes at the initial pressure of 0.1 Torr. The distilledmaterial is then chromatographed over 30 g. of aluminum oxide (activitygrade 3). Elution with a total of 200 ml. of petroleum ether-benzene(2:1), followed by evaporation of the solvent and trituration of theresidue in the presence of petroleum ether, yieldsdesA-androst-9-ene-5,17-dione which upon recrystallization fromcyclohexane melts at 123°-123.5°; [α]_(D) ²⁵ = +83° (c = 0.1021,dioxane).

EXAMPLE 97

20β-Acetoxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid is prepared byozonolysis of 20β-acetoxy-pregn-4-en-3-one according to the procedure ofExample 1.

EXAMPLE 98

A solution of 15.15 g. of 20β-acetoxy-5-oxo-3,5-seco-A-nor-pregnan-3-oicacid in 250 ml. of 75% methanol containing 10 g. of potassium hydroxidewas refluxed for 2 hours. The methanol was then removed in vacuo and theresidue was dissolved in 100 ml. of water. The solution was chilled to0° and acidified to congo red by the addition of 20% hydrochloric acid.There was thus obtained 20β-hydroxy-5-oxo-3,5-seco-A-nor-pregnan-3-oicacid, m.p. 181°-182°,[α]_(D) ²⁵ = 13° (dioxane).

A solution of 4.7 g of 20β-hydroxy-5-oxo-3,5-seco-A-nor-pregnan-3-oicacid in 100 ml. of methanol was neutralized with 1N sodium methylatesolution against phenolphthaleine. The solution was then evaporated andthe residue, consisting of20β-hydroxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid sodium salt, wasrefluxed with 100 ml. of quinoline for 8 hours. The cooled mixture waspoured on a mixture of 150 g. of ice and 100 ml. concentratedhydrochloric acid and extracted with ether. The ether extract was workedup and the oily residue was chromatographed on silica gel. Elution withmethylene chloride gave 10α-desA-pregnane-5,20-dione, m.p. 126°-127°(crystallized from isopropyl ether), [α]_(D) ²⁵ = 82° (dioxane). Elutionwith methylene chloride containing 1% acetone gave20β-hydroxy-10α-desA-pregnan-5-one, m.p. 104°-104.5° (crystallized fromether-hexane), [α]_(D) ²⁵ = -10° (dioxane). The fractions obtained withmethylene chloride containing 5-10% acetone were evaporated and the oilyresidue was dissolved in 40 ml. of acetone. The solution was treatedwith 3 ml. of Jones reagent (0.004 mole CrO₃) at -10° and kept at thesame temperature for 10 minutes. After the addition of 5 ml. ofmethanol, the solution was evaporated and the residue was diluted withwater and extracted with ether. The ether extract was worked up and gave10α-desA-pregnane-5,20-dione.

EXAMPLE 99

20β-hydroxy-desA-pregn-9-en-5-one is prepared from20β-hydroxy-10α-desA-pregnan-5-one by bromination followed bydehydrobromination, according to the precedure of Example 3. Theso-obtained product, after recrystallization from methylenechloride-petroleum ether, melts at 122°-123°.

EXAMPLE 100

5,20-dioxo-3,5-seco-A-nor-pregnan-3-oic acid is prepared by ozonolysisof progesterone according to the procedure of Example 1.

EXAMPLE 101

10α-desA-pregna-5,20-dione and 10β-desA-pregnan-5,20-dione are preparedfrom 5,20-dioxo-3,5-seco-A-nor-pregnan-3-oic acid by conversion of thelatter to its sodium salt followed by pyrolysis, according to theprocedure of Example 2.

EXAMPLE 102

The compound, desA-pregn-9-ene-5,20-dione is prepared from10α-desA-pregna-5,20-dione by bromination followed by dehydrobrominationaccording to the procedure of Example 3. The so-obtained product, afterrecrystallization from ether, melts at 111°-113°.

EXAMPLE 103

15 ml. of 0.8% potassium permanganate solution was added to a mixture of11 g. of 20β-tetrahydropyranyloxy-pregn-4-en-3-one, 500 ml. of anazeotropic mixture of tertiary butanol and water, 7 g. of potassiumcarbonate, 20 ml. of water and 120 ml. of 7% sodium metaperiodatesolution with vigorous stirring at room temperature. 250 ml. of 7%sodium metaperiodate and 20 ml. of 0.8% potassium permanganate solutionwere then simultaneously added within 15 minutes. To the so-obtainedsuspension, 220 ml. of 7% sodium metaperiodate solution and, in order tokeep the mixture violet in color, 15 ml. of 0.8% potassium permanganatesolution were then added in the course of 30 minutes. The mixture wasthen stirred for 90 minutes, filtered over a filter aid (Hyflo) and theresidue was washed with 100 ml. of tert. butanol-water azeotrope. Thefiltrate was evaporated in vacuo at 50° and the residue diluted with 150ml. of water. The solution was acidified with cold 20% hydrochloric acidto congo red, and the resultant oily material taken up in 150 ml. ofmethylene chloride. The organic extract was washed with water, dried andevaporated and the residue was purified by filtration over silica gelusing methylene chloride and methylene chloride containing 1-2% ethanolas the elution agents. There was thus obtained20β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid as aviscous oil.

EXAMPLE 104

To a solution of 35.8 g. of a mixture of 20α- and 20β-hydroxy-pregn-4-en-3-one in 500 ml. of anhydrous benzene, there wereadded 75 ml. of 1% p-toluenesulfoniic acid in benzene and then 35 ml. ofdihydropyan. The reaction mixture was allowed to stand at roomtemperature for 16 hours, washed with 2% aqueous sodium bicarbonate andwater, dried and concentrated in vacuo at 11 mm. Hg and 80°. The residueconsisting of 20α- and 20β-tetrahydropyranyloxy-pregn-4-en-3-one wasdissolved in 2 liters of tert. butanol-water azeotrope followed by theaddition of a solution of 33 g. of potassium carbonate in 80 ml. ofwater and 620 ml. of 7% aqueous sodium metaperiodate solution. To thereaction mixture there was first added with vigorous stirring at roomtemperature, 75 ml. of 0.8% potassium permanganate and thereaftersimultaneously within 30 minutes 1350 ml. of 7 % sodium metaperiodatesolution and 100 ml. of 0.8% potassium permangante solution. Another1080 ml. of 7% sodium metaperiodate solution and 100 ml. of 0.8%potassium permangante solution were then added within 45 minutes. Thereaction mixture was then stirred for 1 hour, filtered over a filter aid(Hyflo) and the residue was washed with 250 ml. of tert. butanol-waterazeotrope. The filtrate was evaporated, the residue taken up in 800 ml.of water and filtered. The alkaline filtrate was chilled to 0°,acidified with cold 20% hydrochloric acid and extracted with methylenechloride. After working up, the extract afforded a mixture of 20α- and20β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid as aviscous oil. This oil was dissolved in 300 ml. of methanol andneutralized with 1N lithium methylate. The solution was evaporated todryness in vacuo. The oily residue was dissolved in 300 ml. of benzene,evaporated again and dried at 11 mm. Hg and 100° for 2 hours. There wasobtained a mixture of the lithium salts of 20α- and20β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid as anamorphous powder.

EXAMPLE 105

A solution of 9 g. of20β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid in 100ml. of methanol was neutralized with 1N lithium methylate solutionagainst phenolphthaleine, followed by evaporation in vacuo to dryness.The so-obtained residue was taken up in benzene, and the benzeneevaporated yielding20β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid lithiumsalt as a semi-crystalline powder.

5 g. of this lithium salt, 7.5 g. of anhydrous sodium acetate and 7.5 g.of anhydrous potassium acetate were mixed and pyrolyzed at 0.02-0.1 mm.Hg and 290° for 4 hours. The distillate was chromatographed on silicagel using methylene chloride and methylene chloride containing 0.5-1%acetone as the elution agents. The fractions were evaporated and gave ontreatment with etherhexane20β-tetrahydropyranyloxy-10α-desA-pregnan-5-one, m.p. 125.5°-127°(crystallized from methanol) [α]_(D) ²⁵ = 53° (dioxane).

The oily part of the evaporation residue containing besides the lattercompound the compound 20β-tetrahydropyranyloxy-10β-desA-pregnan-5-oneethanol. After the addition of 10 ml. of water and 200 mg. ofp-toluenesulfonic acid monohydrate, the solution was refluxed for 60minutes and evaporated in vacuo. The residue was then treated with waterand extracted with ether. The ether extract was worked up and gave20β-hydroxy-10α-desA-pregnan-5-one, m.p. 104.5°-105° (crystallized fromether-hexane).

EXAMPLE 106

250 mg. of 20β-tetrahydropyranyloxy-10α-desA-pregnan-5-one was dissolvedin 8 ml. of ethanol and after the addition of 1 ml. of water and 15 mg.of p-toluenesulfonic acid monohydrate refluxed for 1 hour. The reactionmixture was then evaporated and the residue taken up in ether. The etherextract was worked up and gave 20β-hydroxy-10α-desA-pregnan-5-one, m.p.104.5°-105° (crystallized from ether-hexane).

EXAMPLE 107

10 g. of a mixture of 20α- and20β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid lithiumsalt was mixed with 15 g. each of anhydrous sodium acetate and anhydrouspotassium acetate and pyrolyzed at 0.01-0.1 mm. Hg and 290° for 5 hours.The distillate was dissolved in 100 ml. of ethanol and, after theaddition of 15 ml. of water and 250 mg. of p-toluenesulfonic acidmonohydrate refluxed for 70 minutes. The reaction mixture was thenevaporated, the residue was treated with 50 ml. of 5% sodium bicarbonatesolution and extracted with ether. On working up, the extract gave anoily residue of 20α- and 20β-hydroxy-10α-desA-pregnan-5-one, which wasdissolved in 80 ml. of acetone, treated with 10 ml. of Jones reagent at-10° and kept at -10° for 15 minutes. The suspension obtained wastreated with 15 ml. of ethanol, kept for 10 minutes at room temperatureand evaporated. The residue was diluted with water and extracted withether. The extract was worked up and gave, on addition of hexane,10α-desA-pregnane-5,20-dione, m.p. 126°-127° (crystallized fromisopropyl ether). The above pyrolysis was carried out in the same mannerusing 10 g. of the lithium salt mixture and 30 g. of sodiumphenylacetate.

EXAMPLE 108

40 ml. of 0.8% potassium permanganate solution was added with vigorousstirring to a mixture prepared from 25 g. of testosterone acetate, 1000ml. of tert. butanol-water azeotrope, 16.8 g. of potassium carbonate and300 ml. of 7% aqueous sodium metaperiodate solution. In the course of 15minutes, 660 ml. of 7% sodium metaperiodate solution and 40 ml. of 0.8%potassium permanganate solution were then simultaneously added to theso-formed reaction mixture, followed by the addition of 540 ml. of 7%sodium metaperiodate solution and 20 ml. of 0.8% potassium permanganatesolution in the course of 30 minutes. The mixture was then stirred for90 minutes, filtered over a filter aid (Hyflo) and the residue waswashed with 150 ml. of tert. butanol-water azeotrope. The filtrate wasworked up as described in Example 104 and gave17β-acetoxy-5-oxo-3,5-seco-A-nor-androstan-3-oic acid, a viscous oil.This oil was dissolved in 250 ml. of methanol, the solution was mixedwith a solution of 15 g. of potassium hydroxide in 100 ml. of water andallowed to stand for 16 hours. The solution was then concentrated invacuo. The residue was dissolved in 100 ml. of water, acidified with 20%hydrochloric acid and extracted with methylene chloride. The extract wasworked up and gave 17β-hydroxy-5-oxo-3,5-seco-A-nor-androstan-3-oicacid, m.p. 202.5°-203° (crystallized from ethanol).

EXAMPLE 109

A solution of 14.2 g. of17β-hydroxy-5-oxo-3,5-seco-A-nor-androstan-3-oic acid in 280 ml. ofanhydrous benzene was allowed to stand with 25 ml. of 1%p-toluenesulfonic acid in benzene and 11 ml. of dihydropyran at roomtemperature for 1 hour. The reaction mixture was then poured on ice andextracted with ether. The ether extract was washed with sodium hydrogencarbonate solution and water and evaporated. The oily residue consistedof a mixture of17β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-androstan-3-oic acid andits tetrahydropyranyl ester. The mixture was converted into the freeacid by alkaline hydrolysis.

EXAMPLE 110

5 g of 17β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-androstan-3-oicacid lithium salt (prepared by treating the free acid with 1N lithiummethylate according to the procedure of Example 105) was pyrolyzed in amixture of 7.5 g. each of sodium acetate and potassium acetate at0.05-0.01 mm. Hg and 280°-310° for 80 minutes. The distillate was workedup and the neutral part was chromatographed on silica gel. Usingpetroleum ether-ether (8:2 to 6:4) there was obtained partly cyrstalline17β-tetrahydropyranyloxy-10α-desA-androstan-5-one, [α]_(D) ²⁵ = -16°(dioxane).

The same product was obtained by pyrolysis of the sodium salt at normalpressure under nitrogen and by pyrolysis of the lithium salt inquinoline at 300° and 4.5 atmospheres. However, better yields wereachieved by carrying out the pyrolysis in molten sodium phenylacetate.

EXAMPLE 111

30 ml. of 0.8% potassium permanganate solution was added under vigorousstirring to a solution prepared from 19.8 g. of11β-formyloxy-androst-4-en-3,17-dione, 600 ml. of tert. butanol-waterazeotrope, 12.6 g. of potassium carbonate and 225 ml. of 7% sodiummetaperiodate solution. In the course of 15 minutes, 500 ml of 7% sodiummetaperiodate solution and 20 ml. of 0.8% potassium permanganatesolution were then simultaneously added to the reaction mixture,followed by the addition of another 500 ml. of 7% sodium metaperiodatesolution and 15 ml. of 0.8% potassium permanganate solution in thecourse of 30 minutes. The so-obtained mixture was then stirred for 90minutes, filtered over a filter aid (Hyflo) and the residue was washedwith 60 ml. of tert. butanol-water azeotrope. The filtrate was thenworked up as described in Example 104 and gave11β-formyloxy-5,17-dioxo-3,5-seco-A-nor-androstan-3-oic acid, m.p.220°-221° (from ethanol), [α]_(D) ²⁵ = 107° (dioxane).

The starting 11β-formyloxy-androst-4-ene-3,17-dione was prepared from11β-hydroxy-androst-4-ene-3,17-dione by dissolving the latter in excessformic acid in the presence of a catalytic amount of perchloric acidand, after 20 hours at room temperature, pouring the reaction mixture onice, extracting with methylene chloride and evaporating. There wasobtained a product melting at 139°-139.5° (crystallized from ethylacetate), [α]_(D) ²⁵ = 188° (dioxane).

EXAMPLE 112

A solution of 10 g. of 11β,17β-diformyloxy-androsta-1,4-dien-3-one in100 ml. of acetic acid was ozonized at 0° until thin layerchromatography did not show any starting meterial. The solution was thendiluted with 100 ml. of water, heated to 100° for 30 minutes andevaporated. The residue was worked up according to the procedure ofExample 92, giving 11β,17β-diformyloxy-10ε-desA-androstan-5-one, m.p.164°-166° (crystallized from methanol), [α]_(D) ²⁵ = 21° (chloroform).Further elution using methylene chloride containing 1% acetone gave11β-formyloxy-17β-hydroxy-10ε-desA-androstan-5-one, m.p. 128°-128.5°(crystallized from isopropyl ether), [α]_(D) ²⁵ = 51° (chloroform):

The starting 11β,17β-diformyloxy-androsta-1,4-dien-3-one was preparedfrom 11β,17β-dihydroxy-androsta-1,4-dien-3-one by a procedure analogousto that of Example 111. The product melts at 253°-254° (crystallizedfrom methanol-methylene chloride), [α]_(D) ²⁵ = 72° (dioxane).

EXAMPLE 113

A solution of 800 mg. of11β-formyloxy-17β-hydroxy-10ε-desA-androstan-5-one in 15 ml. of methanolwas mixed with a solution of 600 mg. of potassium hydroxide in 1.5 ml.of water and kept at room temperature for 1 hour. The solution was thentreated with 0.5 ml. of acetic acid and evaporated in vacuo to dryness.The residue was taken up in methylene chloride and the extract wasworked up. There was obtained11β,17β-dihydroxy-10ε-desA-androstan-5-one, m.p. 174.5°-175°(crystallized from ethyl acetate-hexane), [α]_(D) ²⁵ = 36° (chloroform).

EXAMPLE 114

1500 ml. of 16% aqueous sodium metaperiodate solution and 300 ml. of0.8% potassium permanganate solution were added in the course of 50minutes at room temperature to a solution of 25 g. of17β-tetrahydropyranyloxy-androst-4-en-3-one, 1000 ml. of tert.butanol-water azeotrope, 16.8 g. of potassium carbonate and 40 ml. ofwater. The reaction mixture was then stirred for another 1.5 hours andfiltered through a filter aid (Speedex). The precipitate was then washedwith tert, butanol-water azeotrope and worked up as described in Example104 affording17β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-androstan-3-oic acid as anoil.

EXAMPLE 115

120 ml. of 2% ethereal diazomethane solution was added in the course of30 minutes with cooling to a suspension of 10 g of20β-hydroxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid in 100 ml. ofmethylene chloride. The so-obtained solution was kept at roomtemperature for 30 minutes and the excess diazomethane was destroyed bythe addition of a small amount of acetic acid. The solution was thenevaporated and the residue gave, on recrystallization from ethylacetate, 20β-hydroxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid methylester, m.p. 110°-111°, [α]_(D) ²⁵ = 16° (dioxane).

EXAMPLE 116

15 ml. of 1% p-toluenesulfonic acid in benzene and then 7 ml. ofdihydropyran were added to a solution of 10 g. of20β-hydroxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid methyl ester in 130ml. of anhydrous benzene. The reaction mixture was kept at roomtemperature for 4 hours and then poured on 50 ml. of ice water. Theorganic layer was washed with 2% sodium bicarbonate solution and thenwith water, dried and evaporated in vacuo, yielding20β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid methylester as a colorless, viscous oil.

EXAMPLE 117

50 ml. of 20% aqueous potassium hydroxide was added to a solution of 10g. of 20β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acidmethyl ester in 150 ml. of methanol. The reaction mixture was thenrefluxed for 70 minutes and evaporated. The so-obtained residue wasdiluted with 100 ml. of water, acidified with 10% cold hydrochloric acidand extracted with ether. The ether extract was worked up and gave20β-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid as acolorless viscous oil.

EXAMPLE 118

A solution of 5,17-dioxo-3,5-seco-A-nor-androstan-3-oic acid in methanolwas neutralized with 1N lithium methylate solution againstphenolphthaleine. The solution was evaporated to dryness, the residuedissolved in benzene and the so-obtained solution evaporated yielding5,17-dioxo-3,5-seco-A-nor-androstan-3-oic acid lithium salt as anamorphous powder.

5 g. of the above lithium salt was refluxed in 100 ml. of quinoline for6 hours. After cooling, the reaction mixture was filtered and thefiltrate was poured on a mixture of 150 g. of ice and 100 ml. of conc.hydrochloric acid and extracted with ether. The ether extract was workedup and chromatographed on aluminium oxide. The fractions obtained withhexane-benzene (5:1) were evaporated and gave, on addition of hexane,10α-desA-androstane-5,17-dione, m.p. 121.5°-122° (crystallized fromethyl acetatehexane).

EXAMPLE 119

5.56 g. of 17β-hydroxy-5-oxo-3,5-seco-A-nor-androstan-3-oic acid lithiumsalt (prepared by treating the free acid with 1N lithium methylateaccording to the procedure of Example 116) was refluxed in 100 ml. ofquinoline at a bath temperature of 260° for 2 hours. The reactionmixture was then poured on ice and taken up in ether. The ether extractyielded on working up an amorphous residue, which was oxidized with 15ml. of Jones reagent in 150 ml. of acetone at 0°. The reaction mixturewas then worked up and the crude product obtained was refluxed with 60ml. of 2N sodium methylate solution for 1 hour. Chromatography of thereaction product followed by recrystallization from ether-petroleumether yielded pure 10β-desA-androstane-5,17-dione.

The same compound was obtained in an analogous manner starting with17β-hydroxy-5-oxo-3,5-seco-A-nor-androstan-3-oic acid sodium salt.

EXAMPLE 120

4.85 g. of 17β-benzolyoxy-5-oxo-3,5-seco-A-nor-androstan-3-oic acidlithium salt (prepared by treating the free acid with 1N lithiummethylate according to the procedure of Example 116) was refluxed in 100ml. of quinoline for 7 hours. The reaction mixture was then extractedwith ether. The extract was washed with hydrochloric acid, sodiumhydroxide solution and water and the crude product was thenre-benzoylated with benzoyl chloride in pyridine. Chromatography onsilica gel gave 17β-benzoyloxy-10α-desA-androstan-5-one, m.p. 110°-111°(crystallized from acetonehexane), [α]_(D) ²⁵ = 48° (dioxane).

The same product was obtained by pyrolyzing the lithium salt in amixture of 15 g. of sodium acetate and potassium acetate at 0.5-0.05 mm.Hg and 275°-320° for 2 hours and analogous working up of the distillate.

The same or better yields were achieved by carrying out the pyrolysis insodium phenylpropionate, sodium phthalate or sodium propionate.Furthermore, sodium salicylate, sodium benzoate, sodium terephthalateand sodium furoate were also used as the reaction medium.

EXAMPLE 121

1.5 g. of 17α-methyl-17β-hydroxy-desA-9β,10β-androstan-5-one wasdissolved in 30 ml. of acetic anhydride and after the addition of 200mg. of anhydrous sodium acetate refluxed for 2 hours. The reactionmixture was evaporated, the residue was taken up in ether and theextract was worked up yielding17α-methyl-17β-acetoxy-desA-9β,10β-androstan-5-one, m.p. 124°-125°,[α]_(D) ²⁵ = -16° (dioxane).

EXAMPLE 122

A solution of 1 g. of testosterone in 10 ml. of pyridine was refluxedunder nitrogen with a solution of 1 ml. of monochlorodimethyl ether in20 ml. of pyridine at 115°-120° for 2 hours. The reaction mixture wasthen poured on ice and extracted with ether. The ether extract wasworked up yielding testosterone-17β-methoxymethyl ether, m.p. 120°-122°.

This compound was treated with sodium metaperiodate and potassiumpermanganate according to the procedure of Example 114 and the resultingseco acid was pyrolyzed according to the procedure of Example 110. Thereare thus obtained 17β-methoxymethyloxy-desA-androstan-5-one, an oil, asa mixture of the 10α- and the 10β-isomer.

EXAMPLE 123

To 15.0 g. of 5% rhodium/alumina catalyst in a 3 liter round bottomflask was added 120 ml. of 3N hydrochloric acid followed by 300 ml. ofabsolute ethanol. The so-obtained mixture was prereduced by being shakenfor 25 minutes under hydrogen.

To the so-prepared prereduced mixture was added a solution of 30.0 g. of17β-hydroxy-desA-androst-9-en-5-one in 900 ml. of absolute ethanol. Thereaction mixture was then hydrogenated for 60 minutes, at which pointthe rate of uptake leveled off and the reaction was stopped. Thecatalyst was removed by filtration over a filter aid (Celite), thefiltrate was neutralized with saturated aqueous sodium bicarbonate, andthe solution was concentrated in vacuo to ca. 350 ml. This concentratewas then extracted with ether (3 × 350 ml.), the organic phase waswashed with water (3 × 225 ml.) and saturated sodium chloride (2 × 225ml.), and dried over anhydrous sodium sulfate.

The ether solution was filtered and concentrated on the steam bath to afinal solution of 80-100 ml., cooled at room temperature for 3 hours,then overnight at -20°, yielding as white crystals,17β-hydroxy-9β,10β-desA-androstan-5-one which was dissolved in theminimum amount of anhydrous ether and the ether solution wasconcentrated down to about one-tenth original volume and the solutionthen was cooled one hour at room temperature, then overnight at 20°. Thecrystals were then separated and melted at 143°-145.5°, [α]_(D) ²⁵ =-12.9° (CHCl₃, C = 1.065%).

EXAMPLE 124

A solution of 10.0 g. of11α-mesoxy-5,20-dioxo-3,5-seco-A-nor-pregnane-3-oic acid in 100 ml.glacial acetic acid was refluxed under a nitrogen atmosphere for 40minutes. The solution was then concentrated at 50°-55° (water pump), thebrown residue was taken up in ether, washed with water and dried oversodium sulfate. Evaporation of the solvent afforded Δ⁹(11)-5,20-dioxo-3,5-seco-A-nor-pregnene-3-oic acid.

The sodium salt of Δ⁹(11) -5,20-dioxo-3,5-seco-A-nor-pregnene-3-oic acidwas prepared by treating a solution of 7.5 g. of the acid, in 50 ml. ofmethanol, with a slight excess of sodium methoxide (1.3 g.). The finalsolution (pH 8-9; indicator paper) was taken to dryness at the waterpump, bath temperature 55° and stripped with benzene (2 × 10 ml.). Thetan colored semi-solid residue was thoroughly blended with 25.0 g. ofsodium pnenylacetate and pyrolyzed for 3 hours, bath temperature 295°,internal temperature ca. 250°, initial pressure 100 microns (diffusionpump) and final pressure 30 microns. The total contents of the reactionvessel (hard, brown resin) were partitioned between water (300 ml.) andether (100 ml.). The aqueous phase was extracted with ether (3 × 100ml.); the ether phase was washed with water (2 × 100 ml.) and dried oversodium sulfate, yielding a yellow oil which was triturated with etherand cooled at 0°, affording desA-pregnan-9-ene-5,20-dione as slightlyyellow crystals, which upon recrystallization from a small volume ofether melted at 112°-115° (sintering).

EXAMPLE 125

A mixture of 10 g. of 11α-mesoxy-5,20-dioxo-3,5-seco-A-norpregnane-3-oicacid and 100 g. of 1:1 (by weight) mixture of fused sodium acetate andfused potassium acetate was charged to a 250 ml. stirred flask which wasequipped with a gas inlet tube and an air condenser protected with asalt bath. The reaction mixture was then heated at 275°-300° for 3 hourswhile a gentle stream of nitrogen was passed over the surface of themelt. With stirring the mixture was cooled to 90°, 100 ml. of water and35 ml. of methylene chloride were added and stirring was continued untilall of the salt had dissolved. The aqueous layer was then extracted with2 × 100 ml. of methylene chloride and the combined organic extract,after being washed with 2 × 75 ml. of 2N sodium carbonate and 2 × 100ml. of water was dried with sodium sulfate and evaporated. The neutralresidual oil was determined by thin layer chromatographic analysis(silica gel, with ethyl acetate-benzene 2:1, developed by means ofsulfuric acid-methanol, 1:1 V/V and 10% phosphomolybdic acid-methanolsprays) to contain by weight ca. 60% desA-pregn-9-ene-5,20-dione.

EXAMPLE 126

To a solution of 200 mg. of 11α-hydroxy-10α-desA-pregnane-5,20-dione in1 ml. pyridine, 0.2 ml. of acetic anhydride was added, and the mixturewas then allowed to stand overnight at room temperature. It was thenpoured into water and the resultant suspension extracted withchloroform. The extract was washed with water, dried over anhydroussodium sulfate, and evaporated. The crystalline residue wasrecrystallized from ethyl acetate-petroleum ether giving11α-hydroxy-10α-desA-pregnane-5,20-dione acetate, m.p., 157°-158°.

EXAMPLE 127

One mole of 11α-hydroxy-10β-desA-pregnane-5,20-dione was acetylated withone mole of acetic anhydride in pyridine. The crude product, obtainablein quantitative yield, was recrystallized from ether-petroleum ether togive 11α-hydroxy-10β-desA-pregnane-5,20-dione acetate, m.p. 127°-129°.

EXAMPLE 128

A solution of 6.4 g. of 11α-acetoxy-progesterone in 100 ml. ethylacetate and 50 ml. methylene chloride was ozonized at -70° until thesolution became blue in color. After oxygen was passed through, thesolution was evaporated at room temperature in vacuo. The sirupy residuewas dissolved in 100 ml. of glacial acetic acid, and after addition of 5ml. of 30% hydrogen peroxide, kept at 2° for 24 hours. The reactionmixture was then evaporated to dryness, the residue dissolved in 1 literof ether, and the ether solution extracted ten times, each time with 50ml. portion of 2N sodium carbonate solution. The combined carbonateextracts were acidified with concentrated hydrochloric acid and thenoncrystalline precipitate was extracted with methylene chloride. Thecombined extracts were dried over anhydrous sodium sulfate andevaporated to dryness in vacuo. The residue was chromatographed on aFlorisil column and eluted with ethyl acetate. Upon evaporation of thesolvent, the crystalline product obtained gave, after severalrecrystallizations from methylene chloride-hexane,11α-hydroxy-5,20-dioxo-3,5-seco-A-nor-pregnan-3oic acid acetate, m.p.171°-172°, [α]_(D).sup. 25 = 64.6°, (c = 1, in chloroform).

EXAMPLE 129

A solution of 4.5 g. of11α-hydroxy-5,20-dioxo-3,5-seco-A-nor-pregnan-3-oic acid acetate in oneequivalent of aqueous sodium carbonate solution was evaporated todryness in vacuo. The residual sodium salt was mixed well with 15 g. ofsodium phenylacetate and the mixture pyrolyzed at 290° in vacuo (0.02mm.) for 2.5 hours. The crude sublimate was chromatographed on a silicagel column and elution with petroleum ether/ether (3:7) gave a fractionwhich was recrystallized from acetone/petroleum ether. This gave11α-hydroxy-10β-desA-pregnane-5,20-dione, which was identified by mixedmelting point, and by comparison of optical rotation with a sample ofthe same compound prepared by the procedure of Example 7.

EXAMPLE 130

To a solution of 1.5 g. of17β-hydroxy-17α-methyl-10α-desA-androstan-5-one in 100 ml. of carbontetrachloride was added 1.62 g. of sulfuryl chloride dissolved in 75 ml.of carbon tetrachloride, and the reaction mixture stirred and heated at45° for 24 hours. It was then transferred to a separatory funnel, washedwith water, dried over sodium sulfate and evaporated. Separation bypreparative thin layer chromatography gave10β-chloro-17β-hydroxy-17α-methyl-desA-androstan-5-one, which wasrecrystallized from acetonehexane, m.p. 127°-128°, [α]_(D).sup. 25 =59.2° (c = 0.5 in chloroform).

EXAMPLE 131

A mixture of 1.75 g. of crude chlorination product, obtained by theprocedure of Example 130, and 4.3 g. of lithium carbonate in 100 ml. ofdimethylformamide was stirred and heated at 100° for 3 hours. Aftercooling to room temperature, it was diluted with 1.5 liters of ether,and washed successively with water, 1N hydrochloric acid, and water,dried over sodium sulfate, and evaporated. Separation on preparativethin layer chromatograms gave crude non-crystalline17β-hydroxy-17α-methyl-desA-androst-9-en-5-one.

EXAMPLE 132

A solution of 2 g. of 17β-hydroxy-10α-desA-androstan-5-one in 2 ml. ofpyridine and 2 ml. of acetic anhydride was kept overnight at roomtemperature, and then poured into 50 g. of crushed ice. After two hours,the crystalline precipitate was collected by filtration, washed withwater, and dried, giving 17β-acetoxy-10α-desA-androstan-5-one, m.p.69.5°-70.5°, [α]_(D).sup. 25 = -6° (c = 0.5 in chloroform).

EXAMPLE 133

To a solution of 1 g. of 17β-acetoxy-10α-desA-androstan-5-one in 50 ml.of carbon tetrachloride was added dropwise a solution of 0.936 g. ofsulfuryl chloride (2 mole equivalents) in 103 ml. of carbontetrachloride. The reaction mixture was illuminated with a 250-wattinfrared lamp during stirring at 40°-50° for 160 hours. It was thenwashed with water, 2N sodium carbonate solution, and with water again,dried over sodium sulfate and evaporated. A crystalline product wasobtained which contained (gas-liquid chromatography) starting materialand 17β-acetoxy-10β-chloro-desA-androstan-5-one.

To a solution of 1 g. of 17β-acetoxy-10α-desA-androstan-5-one in 150 ml.of carbon tetrachloride was added 75 mg. of benzoylperoxide and dropwisea solution of 0.936 g. of sulfuryl chloride in 100 ml. carbontetrachloride. The reaction mixture was then stirred at room temperaturefor 160 hours. It was worked up in the same way as in Example 133yielding a crystalline product which contained starting material and17α-acetoxy-10β-chloro-desA-androstan-5-one.

To a solution of 0.5 g. of 17β-acetoxy-10α-desA-androstan-5-one in 50ml. of acetic acid-carbon tetrachloride (1:9 v/v) was added in fourportions 0.332 g. (1.33 mole equivalents) of sulfuryl chloride dissolvedin 20 ml. acetic acid-carbon tetrachloride (1:9). The second, third andfourth portions were added 7, 24 and 96 hours respectively, afteraddition of the first. The reaction mixture was stirred at roomtemperature and worked up after 120 hours. A crystalline productcontaining starting material and17β-acetoxy-10β-chloro-desA-adndrostan-5-one was obtained.

Recrystallization of the crude products obtained in the aboveexperiments from ether gave 17β-acetoxy-10β-chloro-desA-androstan-5-one,m.p. 137°-141°, [α]_(D).sup. 25 = 93.8° (c = 0.5 in chloroform).

EXAMPLE 134

A mixture of 0.5 g. of 17β-acetoxy-10β-chloro-desA-androstan-5-one and1.18 g. of lithium carbonate in 50 ml. of dimethylformamide was stirredat 100° for two and three-quarter hours. After cooling to roomtemperature, the mixture was diluted with 750 ml. of ether, and theether solution washed with water, 1N hydrochloric acid, aqueous 2Nsodium carbonate, and again with water, dried over sodium sulfate andevaporated giving 17β-acetoxy-desA-androst-9-en-5-one, m.p. 65°-70°,[α]_(D).sup. 25 = -25.2° (c = 1.05 in chloroform).

Alternatively, the crude products of the chlorinations of Example 133were, without purification, dehydrochlorinated under the aboveconditions, and 17β-acetoxy-desA-androst-9-en-5-one isolated bypreparative thin layer chromatography.

EXAMPLE 135

A solution of 1.5 g. of 11α-mesoxy-5,20-dioxo-3,5-seco-A-nor-pregnan-3-oic acid in 45 ml. of methanol was mixedwith 0.385 g. of sodium carbonate in 15 ml. of water and evaporated todryness. The last trace of water was removed by adding benzene andevaporating to dryness again. To the residual salt was added 50 ml. offreshly distilled triethanolamine, and the reaction mixture was thenheated for 3- 4 hours in a metal bath of 215°-220° under a nitrogenatmosphere. The temperature of the reaction solution varied between 190°and 205°. After cooling, the reaction mixture was diluted with 1 literof water, and extracted with ether (10 × 150 ml.). The combined etherextracts were washed with water, 1N, hydrochloric acid, and with wateragain, dried and evaporated, yielding a crude product which wasdetermined by ultraviolet spectroscopy and by gas chromatography tocontain a substantial amount of desA-pregn-9-ene-5,20-dione. When thereaction time was extended to 5 to 6 hours, the yield dropped slightly.

A solution of 2.418 g. of the crude product obtained by the foregoingprocedure and 1.4 g. of semicarbazide in 60 ml. of 95% ethanol and 9 ml.of glacial acetic acid was stirred and refluxed for 2 hours. Aftercooling in ice, the precipitate was filtered off and washed withethanol. Evaporation of the mother liquors and crystallization from 10ml. of 95% ethanol gave additional product. Both crops were combined,suspended in 100 ml. of 95% ethanol, refluxed for one hour, andconcentrated to a volume of 50 ml., cooled in an ice bath, and filtered,giving desA-pregn-9-ene-5,20-dione disemicarbazone, which does not meltbelow 340°, but showed slight decomposition above 270°.

A solution of 1.87 g. of the so-formed disemicarbazone in 75 ml. aceticacid, 25 ml. of water, and 6.5 ml. of 1.66N pyruvic acid was warmed fortwo minutes at 40°, then left overnight at room temperature. It was thendiluted with 1.5 liters of ether, washed with water, aqueous 2N sodiumcarbonate, and with water again, dried, and evaporated. The crystallineresidue was dissolved almost completely in 50 ml. of hot heptane,filtered, and the filtrate was evaporated. The last operation wasrepeated with the residue and 20 ml. of heptane, and the so-obtainedresidue recrystallized from ether, yielding desA-pregn-9-ene-5,20-dione,which melted at 113°-113.5°, [α]_(D).sup. 25 = 54.1° (c = 1 inchloroform).

EXAMPLE 136

20β-Hydroxy-desA-pregn-9-en-5-one was reacted with semicarbazide in a(10:1 v/v) ethanol/acetic acid solution to give20β-hydroxy-desA-pregn-9-en-5-one semicarbazone as colorless needles,m.p. 196°-198° ex ethyl acetate, [α]_(D).sup. 25 = 110° (c = 0.5 inethanol).

EXAMPLE 137

A solution of 524 mg. of desA-pregn-9-ene-5,20-dione in absolutemethanol (65 ml.) was stirred at 5°. Over a period of forty minutes,sodium borohydride (0.5 g.) was then added thereto. The total reactiontime allowed was one hour. Cold glacial acetic acid was then addeddropwise until the pH was about 7.5, the solution was concentrated todryness in vacuo, chloroform (150 ml.) added, and the solution washedwith water until it was neutral. The organic layer was then dried withsodium sulfate, and evaporated to dryness, yielding a clear oil.Chloroform (50 ml. dried over silica gel) was added to 552 mg. of thisoil, and stirred with 10 g. of precipitated manganese dioxide (Code No.37, General Metallic Oxides) for 19 hours. The suspension was thenfiltered through a sintered-glass funnel using a filter aid (Celite),and evaporated to dryness in vacuo giving a colorless oil.Crystallization of 520 mg. of this oil gave20β-hydroxy-desA-pregn-9-en-5-one as colorless needles, m.p. 116°-122°.A further amount of this compound was isolated from thin layerchromatograms. At the same time, a second band which was fluorescentunder ultraviolet light was eluted giving20α-hydroxy-desA-pregn-9-en-5-one, which was acetylated with aceticanhydride in pyridine giving 20α-hydroxy-desA-pregn-9-en-5-one acetate,as colorless needles, m.p. 87°-89° ex ether/petroleum ether,[α]_(D).sup. 25 = -37.8° (c = 0.312 in ethanol).

EXAMPLE 138

20β-Hydroxy-desA-pregn-9-en-5-one (0.250 g.) was dissolved in 2 ml. of(1:1 v/v) acetic anhydride in pyridine and allowed to stand overnight.The solution was then poured onto crushed ice and the crystallineprecipitate collected and sucked dry. The residue was crystallized frommethanol/water giving 20β-acetoxy-desA-pregn-9-en-5-one as needles whichwere recrystallized from petroleum ether yielding the product ascolorless needles, m.p. 84°-85°, [α]_(D).sup. 25 = 12.6° (c = 0.5 inethanol).

EXAMPLE 139

A suspension of 238 mg. of 5% rhodium on alumina catalyst in a mixtureof 26 ml. of 95% ethanol and 5.25 ml. of 2N aqueous sodium hydroxide wasprereduced. To this was then added a solution of 262 mg. of17β-hydroxy-desA-androst-9-en-5-one in 15 ml. 95% ethanol, and the wholemixture hydrogenated at room temperature and atmospheric pressure. Afterone mole equivalent of hydrogen was absorbed, the reaction was stopped,and the catalyst was separated by filtration. After standing overnightthe filtrate was concentrated in vacuo. To the residue was added 1 ml.of glacial acetic acid, and the so-formed mixture dissolved in 1 literof ether. The resultant clear solution was washed with 2N aqueous sodiumcarbonate solution, then with water, then dried over anhydrous sodiumsulfate and evaporated to dryness in vacuo, yielding a pale yellow oilcontaining a substantial amount of17β-hydroxy-9β,10β-desA-androstan-5-one.

EXAMPLE 140

20β-Hydroxy-9β, 10βdesA-pregnan-5-one (45 mg.) was dissolved in pyridine(0.1 ml). and acetic anhydride (0.1 ml.) and the reaction mixtureallowed to stand overnight at room temperature, evaporated to dryness invacuo, and passed through a silica gel column. The crystalline fractionwas recrystallized from aqueous methanol giving 20β-acetoxy-9β,10β-desA-pregnan-5-one as colorless needles which upon crystallizationfrom petroleum and then from ether/petroleum ether formed colorlessneedles, m.p. 100°-100.5° , [α]_(D).sup. 25 = 27.1° (c = 0.5 inethanol).

EXAMPLE 141

Hydrogenation of 1 g. of 20β-hydroxy-desA-pregn-en-5-one was performedunder acidic conditions according to the procedure of Example 15. Afterseparation of catalyst an excess of 20 ml. 2N sodium hydroxide solutionwas added and allowed to stand overnight. The solution was acidified,dissolved in ether, and washed with sodium carbonate and water, driedand evaporated to dryness yielding a colorless oil which was dissolvedin benzene (3 ml.) with warming. A solution (3 ml., equivalent to about50% excess) of sodium t-amylate in benzene was added in the cold under anitrogen atmosphere and the reaction mixture allowed to stand for onehour at room temperature. Freshly distilled (b.p. 80°) methyl vinylketone (2 ml. in 4 ml. of dry benzene) was then added thereto in sixequal portions at a regular interval during the course of two hours. Theresultant suspension was then refluxed for two hours, and allowed tostand overnight. The reaction mixture was acidified with glacial aceticacid, dissolved in ether, washed with 2N aqueous sodium carbonate andwater, dried over sodium sulfate and evaporated to give a yellow oil.From this oil two fractions were separated by preparative thin layerchromatography [twenty-five (1 mm. thick) silicic acid plates]. Firstfraction was further purified by column chromatography giving20β-hydroxy-9β,10β -desA-pregnan-5-one. The second fraction was furtherfractionated by preparative thin layer chromatography to give an oilyproduct which was dissolved in methylene chloride (50 ml.), and oxidizedwith chromic acid in acetic acid solution (1 ml.), washed withbisulfite, and the organic layer dried and evaporated yielding an oilyproduct which was purified by thin layer chromatography giving an oil,which crystallized upon addition of a drop of ethanol. Recrystallizationfrom ethanol yielded 9β,10α-pregn-4-ene-3,20-dione as colorless needles,m.p. 163- 164°.

EXAMPLE 142

The crude product of the hydrogenation of Example 141 was dissolved inbenzene (3 ml.) with warming. A solution (3 ml., equivalent to about 50%excess) of sodium t-amylate in benzene was then added thereto in thecold under a nitrogen atmosphere and the reaction mixture allowed tostand for one hour at room temperature. 4-Diethylaminobutan-2-one (3 g.in 4 ml. dry benzene) was added in six equal portions at regularintervals during the course of two hours. The resultant suspension wasthen refluxed for two hours, and allowed to stand overnight. Thereaction mixture was acidified with glacial acetic acid, dissolved inether, washed with 2N aqueous sodium carbonate and water, dried oversodium sulfate, and evaporated to give a yellow oil. By using the sameprocedure as in Example 141 after chromic acid oxidation, crystallinematerial was isolated which was purified, giving9β,10α-pregn-4-ene-3,20-dione, m.p. and mixed m.p. 163°-164°.

EXAMPLE 143

The crude product of the hydrogenation according to the procedure ofExample 141 of 1.2 g. of 20β-hydroxy-desA-pregn-9-en-5-one was dissolvedin benzene (5 ml.). A solution (3 ml., equivalent to about 50% excess)of sodium t-amylate in benzene was then added thereto in the cold undera nitrogen atmosphere, and the reaction mixture allowed to stand for onehour at room temperature. 4-Diethylaminobutan-2-one methiodide (6 g.,m.p. 85°-86° ex acetone/chloroform) as a suspension in benzene (5 ml.)was added in six equal portions at regular intervals during the courseof two hours. The resultant suspension was then refluxed overnight. Thereaction mixture was acidified with glacial acetic acid, dissolved inether, washed with 2N aqueous sodium carbonate and water, dried oversodium sulfate, and evaporated to give a yellow oil. By using the sameprocedure as in Example 141, after chromic acid oxidation, crystallinematerial was isolated, which afforded after recrystallization9β,10α-pregn-4-ene-3,20-dione, m.p. and mixed m.p. 163°-164°.

EXAMPLE 144

To the solution of 108 mg. of 20β-hydroxy-9β,10β-desA-pregnan-5-one(regenerated from its acetate by hydrolysis using aqueous sodiumhydroxide) in ethanol (8.2 ml.) was added 1 ml. of sodium ethoxidesolution (prepared by dissolving 2.36 g. of sodium to make 250 ml. of anethanolic solution) i.e. 1 mole of sodium ethoxide per mole of20β-hydroxy-9β,10β-desA-pregnan-5-one. The reaction mixture was thenallowed to stand for half an hour and freshly distilled4-diethylaminobutan-2-one (0.5 ml.) added thereto, and the resultantmixture allowed to stand for two hours. Refluxed for one and one-halfhours, and added two more portions (0.5 ml. each) of4-diethylaminobutan-3-one in the cold under a nitrogen atmosphere. Thesolution was refluxed for one hour between the last two additions, andthen overnight. The solution was cooled to room temperature andacidified using glacial acetic acid, poured into 10N sodium carbonatesolution (100 ml.) on an ice-bath, extracted with ether (4 × 100 ml.)and methylene chloride (4 × 100 ml.), and washed with water. Evaporationthen gave a pale yellow oil which was processed according to procedureof Example 141 and which after oxidation with chromic acid yielded9β,10α-pregn-4-ene-3,20-dione, m.p. and mixed m.p. 163- 164°.

EXAMPLE 145

To a solution of 0.104 g. of 20β-hydroxy-9β,10β-desA-pregnan-5-one(prepared via a crystalline acetate by saponification) in ethanol (2ml.) was added 0.4 ml. "Triton B" (35% of benzyltrimethylammoniumhydroxide in methanol). A solution of freshly distilled methyl vinylketone (0.08 g.) in ethanol (4 ml.) was then added to the reactionmixture under a nitrogen atmosphere. After refluxing for two hours, thereaction mixture was cooled and acidified with 3N hydrochloric acid (1ml.) and again heated on a steam bath for ten minutes. The reactionmixture was then again cooled and poured into crushed ice (10 g.) andtaken up in 1 liter of ether. The ether layer was washed successivelywith 1N hydrochloric acid (50 ml.), water (50 ml.), 1N sodiumbicarbonate solution, and water (3 × 50 ml.). The ether solution wasthen dried over sodium sulfate and evaporated giving a yellow oil whichby using preparative thin layer plates was separated into unchangedstarting material and a yellow oil, which crystallized spontaneously.Recrystallization from ethanol gave 20β-hydroxy-9β,10α-pregn-4-en-3-oneas colorless needles ex ethanol, m.p. and mixed m.p. 175°-176°. Afteroxidation with chromic acid, the latter gave9β,10α-pregn-4-ene-3,20-dione, m.p. and mixed m.p. 163°-164° ex ethanol.

EXAMPLE 146

To a solution of 200 mg. of desA-pregnan-9-ene-5,20-dione in 15.0 ml. ofabsolute ethanol there was added 40.4 mg. of 5% rhodium on aluminacatalyst. To this mixture there was then added 0.4 ml. of 3Nhydrochloric acid. The reaction mixture was then hydrogenated in a roundbottom flask with moderate shaking at atmospheric pressure and roomtemperature. The hydrogenation was terminated at the end of 60 minutesand the reaction mixture neutralized to pH 7 with sodium carbonate,filtered over a filter aid (Celite) and concentrated in vacuo at 40°.The residue was taken up in ether, partitioned between ether and water,and the ether layer washed with brine, dried over sodium sulfate, andevaporated in vacuo at 25° yielding an oil which was recrystallized fromether yielding crude reaction product containingdesA-9β,10β-pregnane-5,20-dione.

Utilizing the same procedure as above desA-pregnan-9-ene-5,20-dione wasalso hydrogenated to desA-9β,10β-pregnane-5,20-dione utilizing thefollowing:

             Weight Ratio           M.Moles of                                             Catalyst to   Hydrogenation                                                                          Acid/Mg. of                                   Catalyst Substrate                                                                             Medium                                                                              Time, Minutes                                                                          Catalyst                                      __________________________________________________________________________    5%                                                                              rhodium/                                                                             1:5     3N HCl/                                                                             60        3/100                                          alumina        ethanol                                                      5%                                                                              rhodium/                                                                              1:20   "     80       12/100                                          alumina                                                                     5%                                                                              rhodium/                                                                             1:5     "     55       30/100                                          carbon                                                                        powder                                                                      5%                                                                              ruthenium/                                                                           1:5     ethanol                                                                             270      neutral (i.e.                                   carbon                        no acid)                                        powder                                                                      __________________________________________________________________________

EXAMPLE 147

A mixture of 200 mg. of 20β-acetoxy-desA-pregnan-9-en-5-one, 25 mg. of5% rhodium on alumina catalyst, 0.4 ml. of 3N hydrochloric acid and 15ml. of absolute ethanol was hydrogenated at atmospheric pressure androom temperature with moderate shaking of the flask containing thereaction mixture. The hydrogenation was terminated at the end of 45minutes, the catalyst removed by filtration and the filtrate neutralizedto pH 7 with 5% aqueous sodium bicarbonate. The so-obtained neutralmixture was then concentrated in vacuo at 45°, and partitioned between40 ml. of dichloromethane and 20 ml. of water. The organic layer wasthen separated, washed with water, dried over aqueous sodium sulfate andconcentrated in vacuo at 40° yielding20β-acetoxy-desA-9β,10β-pregnan-4-one.

EXAMPLE 148

1.0 g. of 17β-hydroxy-desA-9β,10β-androstan-5-one was dissolved in 50ml. of anhydrous benzene. Then 20 ml. of solvent was boiled off and,after flushing the reaction flask with nitrogen, 25 mg. of potassiumt-butylate was added thereto. Another 10 ml. of the solvent was thenboiled off and in the course of one hour, with stirring and refluxing, asolution of 0.5 ml. of 4-diethylaminobutan-2-one in 10 ml. of benzenewas gradually added to the reaction mixture. The reaction mixture wasthen stirred and refluxed for a further hour, after which the reactionmixture was cooled and filtered through 10 g. of alumina (neutral, GradeIII). The column was washed with 100 ml. of ether and the combinedfiltrates were evaporated, yielding a yellow reaction product which wasdissolved in 30 ml. of benzene and chromatographed on a column of 100 g.of alumina (neutral, Grade III). Elution with benzene and benzene:ether(19:1) (10 fractions, 100 ml. each) yielded some unreacted startingmaterial. The desired product, 9β,10α-testosterone, was then eluted withbenzene:ether [(9:1), (4:1), and (2:1)] (6 fractions, 100 ml. each).Evaporation of these fractions and crystallization of the residue fromdiisopropyl ether yielded 9β,10α-testosterone, m.p. 153°-154°.

EXAMPLE 149

To a mixture of 100 g. of 17β-hydroxy-desA-9β,10β-androstan-5-one and 20mg. of potassium hydroxide in 30 ml. of t-butanol at 60°, a solution of0.455 g. of 4-diethylaminobutan-2-one in 5 ml. of benzene was addedgradually in the course of 30 minutes under a nitrogen atmosphere withstirring. The reaction mixture was then stirred at 60° for an additional30 minutes and then cooled to 20°. To the so-cooled reaction mixture,0.1 ml. of acetic acid was added and the resulting mixture evaporated invacuo at 30°. The crude product was then chromatographed as described inExample 148 and the fractions containing 9β,10α-testosterone (by thinlayer chromatography) were combined, evaporated and the residuecrystallized from ether yielding 9β,10α-testosterone, m.p. 155°-156°.

The same procedure as above was repeated utilizing isopropanol in placeof t-butanol and effecting the reaction at 50° rather than 60°. Thereaction so-conducted also yielded 9β,10α-testosterone.

EXAMPLE 150

To a mixture of 1.0 g. of 17β-hydroxy-desA-9β,10β-androstan-5-one and 20mg. of potassium hydroxide in 30 ml. of t-butanol at 50°, a solution of0.243 g. of 4-dimethylaminobutan-2-one was added gradually in the courseof 30 minutes under a nitrogen atmosphere and with stirring. Thereaction mixture was then stirred at 50° for an additional 30 minutesand then cooled to 20°. To the so-cooled reaction mixture 0.1 ml. ofacetic acid was added and the resulting mixture evaporated in vacuo at30°. The crude product was chromatographed as described in Example 148and the fractions containing 9β,10α-testosterone (by thin layerchromatography) were combined, evaporated, and the residue crystallizedfrom ether yielding 9β,10α-testosterone.

The same procedure as above was repeated but in place of the4-dimethylaminobutan-2-one, 0.30 g. of 4-(N-pyrrolidyl)-butan-2-one wasutilized. This reaction so-conducted also yielded 9β,10α-testosterone.

EXAMPLE 151

To a stirred solution of 1.0 g. of desA-9β,10β-androst-5,17-dione and 20mg. of sodium hydroxide in 30 ml. of t-butanol maintained at 50° andunder a nitrogen atmosphere, there was added gradually within the courseof 30 minutes a solution of 0.30 g. of methyl vinyl ketone in 5 ml. ofbenzene. The reaction mixture was then stirred under a nitrogenatmosphere at 50° for an additional 30 minutes and then cooled to 20°.To the so-cooled reaction mixture 0.1 ml. of acetic acid was added andthe resulting mixture evaporated in vacuo at 30°. The crude product wasthen chromatographed as described in Example 148 and the fractionscontaining 9β,10α-androst-4-ene-3,17-dione (by thin layerchromatography) were combined, evaporated, and the residue crystallizedfrom ether yielding the product as crystals melting at 153°-154°.

EXAMPLE 152

A 57% sodium hydride in mineral oil dispersion (285 mg.) was washed freeof oil with ether, and then suspended in 20 ml. dry dimethylformamideunder a nitrogen atmosphere.17β-(Tetrahydro-2-pyranyloxy)-9β,10β-desA-androstane-5-one (2.17 g.) in20 ml. dry dimethylformamide was added in one portion to the sodiumhydride suspension, and the reaction mixture was then stirred at 100°under a nitrogen atmosphere for 1 hour. The resulting solution wascooled to 20°, and 791 mg. of 1-chloro-3-butanone in 1 ml. drydimethylformamide in one portion, was added thereto with stirring. Afterstanding at 20° for 16 hours under a nitrogen atmosphere, the solutionwas evaporated in vacuo. The last traces of dimethylformamide wereremoved in high vacuo at about 80° bath temperature. The residual oilwas dissolved in ethyl acetate, the ethyl acetate solution was washedwith water, dried with sodium sulfate, and evaporated in vacuo giving anoil; 2.32 g. of which was dissolved in 24 ml. of 0.5N sodium methoxidein methanol. The mixture was then allowed to stand at 20° for 72 hoursunder a nitrogen atmosphere. It was then poured on ice and the pH wasadjusted to 7.5 with 1N HCl. Most of the methanol was then evaporatedoff in vacuo and the residue was extracted at 20° with ethyl acetate.The ethyl acetate extract was washed with water, dried with sodiumsulfate, charcoaled (with Norite A) and evaporated in vacuo giving anoil. This oil was placed in a mixture of 18 ml. of methanol and 6 ml. of2N HCl and the resultant mixture was refluxed under a nitrogenatmosphere for 90 minutes. It was then poured on ice, neutralized with1N NaOH, and concentrated in vacuo. The residue was extracted at 20°with ethyl acetate and ether. The combined extracts were then washedwith aqueous sodium chloride, dried with sodium sulfate, charcoaled(with Norite A), and evaporated in vacuo giving an oil, which accordingto thin layer chromatography consisted of two main components,17β-hydroxy-9β,10β-desA-androstane-5-one and 9β,10α-testosterone.

The above-described crude oil was chromatographed using a Florisilcolumn (34 g. of adsorbent) with benzene, benzenechloroform andbenzene-ethyl acetate eluents. First17β-hydroxy-9β,10β-desA-androstane-5-one was eluted, followed by crude9β,10α-testosterone. Mixed melting point determination with an authenticsample of 9β,10α-testosterone showed no depression of the melting point.Recrystallization from ether gave purified 9β,10α-testosterone, m.p.155°-156°,[α]_(D) ²⁵ = -150° (chloroform).

EXAMPLE 153

A 57% sodium hydride in mineral oil dispersion (84 mg., 2 m.moles) waswashed free of oil with ether and then suspended in 8 ml. of drydimethylformamide under a nitrogen atmosphere.17β-Hydroxy-9β,10β-desA-androstane-5-one (236 mg., 1 m.mole) in 8 ml. ofdry dimethylformamide was added to the stirred suspension, and thereaction mixture was heated under a nitrogen atmosphere at 55° for 1hour. It was then cooled to 20°, and 117 mg. of 1-chloro-3-butanone wasadded in one portion. The reaction mixture was then stirred at 20° undera nitrogen atmosphere for 1 hour, poured on ice and neutralized with 1NHCl. The water and some dimethylformamide were evaporated in vacuo. Thelast of the dimethylformamide was removed in high vacuo at about 80°bath temperature. The residual oil was then dissolved in ethyl acetate,the ethyl acetate solution was washed with water, dried with sodiumsulfate, and evaporated in vacuo giving crude product which was put in amixture of 6 ml. methanol and 2 ml. of 2N HCl. The resultant mixture wasrefluxed under nitrogen for 90 minutes. It was then poured on ice,neutralized with 1N NaOH, and concentrated in vacuo. The residue wasextracted with ethyl acetate and with ether. The combined extracts werewashed with aqueous sodium chloride, dried with sodium sulfate, andevaporated in vacuo giving an oil containing as the two main components,17β-hydroxy-9β,10β-desA-androstane-5-one and 9β,10α-testosterone. Thelatter compound can be separated by chromatographic means.

EXAMPLE 154

20β-Hydroxy-9β,10β-desA-pregnan-5-one (100 mg.) and 0.15 ml. of freshlydistilled 1,3-dichloro-2-butene (b.p. 130°) in 0.3 ml. of dry benzenewas cooled in an ice-bath. To the reaction mixture there was then added,in an atmosphere of dry nitrogen, sodium t-amylate solution (0.3 ml.)prepared by refluxing in an atmosphere of nitrogen 4.41 g. of t-amylalcohol and 25 ml. of dry benzene over 1.77 g. sodium. The reactionmixture was then diluted with 7 ml. of benzene, washed with 2 ml. ofwater, dried with sodium sulfate, and concentrated to a volume of 2 ml.Chromatography of the so-concentrated solution on 50 g. of silicic acidusing 1% ethyl acetate in benzene as the eluent gave a 50:50 (indicatedby thin layer chromatography) mixture containing3-chloro-20β-hydroxy-3-methyl-3,5-seco-9β,10α-A-nor-pregn-2-en-5-onesand the corresponding 10β-isomer.

The so-obtained substance was dissolved in methylene chloride, oxidizedovernight with chromic acid solution (prepared from 40 mg. chromiumtrioxide dissolved in 0.2 ml. of water and 2 ml. of acetic acid), theresulting product containing3-chloro-3-methyl-3,5-seco-9β,10α-A-nor-pregn-2-ene-5,20-dione wasdissolved in an equal volume of cold concentrated sulfuric acid, dilutedwith water, extracted with methylene chloride, and refluxed in benzenein the presence of p-toluene sulfonic acid for one hour. The reactionmixture was washed with aqueous sodium carbonate solution, water, driedover sodium sulfate and evaporated to dryness yielding an oil. Thinlayer chromatography yielded 9β,10α-progesterone.

EXAMPLE 155

A solution of 17β-hydroxy-9β,10β-desA-androstane-5-one in anhydrousbenzene was reacted with dihydropyran in the presence of 1% p-toluenesulfonic acid in benzene according to the procedure of Example 109. Thisreaction yielded 17β-tetrahydropyranyloxy-9β,10β-desA-androstane-5-one,which upon recrystallization from ether/petroleum ether melted at109°-111°,[α]_(D) ²⁵ = +62.9 (in chloroform, c = 1%).

We claim:
 1. A compound of the formula: ##SPC31##wherein R₃ is selectedfrom the group consisting of hydrogen, fluoro, lower alkyl, hydroxy,benzoyloxy and lower alkanoyloxy; R₆ is selected from the groupconsisting of hydrogen, lower alkyl, hydroxy, benzoyloxy, loweralkanoyloxy and halogen; EO is benzoyloxy, lower alkanoyloxy or freehydroxy; when R₃ and R₆ are hydroxy they may be taken together with analdehyde or ketone to form an acetal or ketal of the formula: ##EQU3##wherein P is individually selected from the group consisting of hydrogenand lower alkyl; Q is individually selected from the group consisting oflower alkyl, phenyl, phenyl substituted with radicals selected from thegroup consisting of halogen, lower alkoxy, hydroxy and lower alkyl,phenyl-lower-alkyl or phenyl-lower-alkyl aromatically substituted withradicals selected from the group consisting of halogen, lower alkoxy,hydroxy and lower alkylcyano; and P and Q taken together are loweralkylene; R₅ is selected from the group consisting of hydrogen andhalogen; X is a substituent in the 6-position selected from the groupconsisting of hydrogen, lower alkyl, lower alkylthio and loweralkanoylthio or a substituent in the 7-position selected from the groupconsisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthioand halogen.
 2. A compound according to claim 1 wherein P and Q takentogether are lower alkylene.
 3. A compound of the formula:##SPC32##wherein R₃ is selected from the group consisting of hydrogen,fluoro, lower alkyl, hydroxy, benzoyloxy, and lower alkanoyl; R₆ isselected from the group consisting of hydrogen, lower alkyl, hydroxy,lower alkoxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy,tetrahydropyranyloxy and halogen; EO is selected from the groupconsisting of benzoyloxy, lower alkanoyl, and hydroxy; and X is asubstituent in the 6-position selected from the group consisting ofhydrogen, lower alkyl, lower alkylthio and lower alkanoylthio or asubstituent in the 7-position selected from the group consisting ofhydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen.4. A compound of the formula: ##SPC33##wherein R₃ is selected from thegroup consisting of hydrogen, fluoro, lower alkyl, hydroxy, benzoyloxy,and lower alkanoyl; EO is selected from the group consisting ofbenzoyloxy, lower alkanoyl, and hydroxy; and X is a substituent in the6-position selected from the group consisting of hydrogen, lower alkyl,lower alkylthio and lower alkanoylthio or a substituent in the7-position selected from the group consisting of hydrogen, lower alkyl,lower alkylthio, lower alkanoylthio, and halogen.
 5. A compound of theformula: ##SPC34##wherein R₃ is selected from the group consisting ofhydrogen, fluoro, lower alkyl, hydroxy, benzoyloxy, and lower alkanoyl;EO is selected from the group consisting of benzoyloxy, lower alkanoyland hydroxy; and X is a substituent in the 6-position selected from thegroup consisting of hydrogen, lower alkyl, lower alkylthio and loweralkanoylthio or a substituent in the 7-position selected from the groupconsisting of hydrogen, lower alkyl, lower alkylthio, loweralkanoylthio, and halogen.